Instruments and methods for obtaining informed consent to genetic tests

ABSTRACT

This invention provides an instrument for obtaining consent for a genetic test that comprises three or more integrated elements including an information element for conveying information to an individual concerning a genetic test, and instruction element for use by a practitioner in instructing individuals on the genetic test and use of the instrument, a collection element for collecting an individual&#39;s medical and family history, a assessment element for assessing the individual&#39;s retention and understanding of information concerning a genetic test, a certification element for certifying the individual&#39;s consent to said tests, as well as housekeeping elements useful for recording a medical record, labeling a sample, and billing. Also provided is a method for obtaining informed consent for a genetic test using an integrated instrument. The instruments and methods disclosed have utility in obtaining informed consent for genetic tests.

FIELD OF THE INVENTION

This invention provides novel instruments and methods for obtaininginformed consent for genetic tests.

BACKGROUND OF THE INVENTION

The human genome project has been undertaken with the expectation thatthe sequences of genes that comprise the genome are determinants ofindividual development, health, and disease. Variation in genesequences, variations in the level, location, or timing of expression ofa gene, and variation in the physical, chemical, or dynamiccharacteristics of the products expressed from a gene are known tounderlie many aspects of human individuality including physical andmental characteristics, growth, longevity, health, and disease. Anobjective of genomic research is the discovery, development andimplementation of genetic tests that can be used to determine how thegenes of an individual predispose that individual to various clinicaloutcomes. Genetic tests are expected to have a central role in routinehealth, wellness, and disease management, enabling predispositiontesting and interventions to prevent disease, providing early diagnosis,and optimizing pharmacological interventions with drugs that are likelyto be safe and effective for an individual.

The utilization of genetic tests and the interpretation of genetic testsresults are more complex than conventional diagnostic testing. Thenumber of genetic tests that will be available from human genomicresearch is very large compared to the number of conventional diagnostictests. The genome project is expected to reveal 30,000-100,000 genesand >10,000,000 discrete genetic variations that may be developed intogenetic tests with utility in predicting specific health outcomes. Fewindividuals or healthcare practitioners are familiar with the many genesdifferent already known to be associated with specific health outcomes.Few have the ability to remain current with the rapidly emergingliterature in this field. The effective and ethical use of genetic testsrequires that individuals have sufficient information about the tests todecide whether to have the test done and to make efficacious use of thetest result. This requires that individuals have access to informationconcerning the potential benefits of genetic testing, the proceduresinvolved in genetic testing, and the potential risks to health andprivacy. Because of the unique nature of genetic testing, good medicalpractice and statutory requirements in some states require that aninformed consent be obtained from an individual before a sample isobtained and a genetic test is performed. To provide a valid informedconsent, an individual must have been given and must retain andunderstand sufficient information concerning the test, the DNA sample,the potential use of genetic information that may be obtained from thesample, and the potential benefits and risks associated with the test tomake an informed decision regarding the test.

Genetic testing is typically initiated by health care practitioners(including primary or subspecialty physicians or practitionersspecialized in genetics, such as MD, PhD, or MA/MS trained geneticistsor genetic counselors), and informed consent is obtained by thepractitioner during a meeting with the individual. During this meeting,the practitioner must provide the individual with information sufficientfor the individual to make an informed choice and to certify theirconsent to the testing procedure. After certification, samples aretypically obtained by the health care practitioner or a designated blooddrawing facility and tests are then performed by certified laboratories.The test result is reported from the laboratory to the practitionerand/or to the individual. Many practitioners do not have sufficienttraining in genetics, knowledge relating to individual genetic tests, ortime to adequately provide individuals with the information required toprovide a legally binding informed consent.

The process of obtaining informed consent is described in manytextbooks, articles, reports, and recommendations. In current practice,information about genetic tests is collected by practitioners andindividuals from a variety of sources including textbooks of medicine orgenetics, as well as articles in medical journals, courses forcontinuing medical education, government agencies, disease advocacygroups, biotechnology companies, academic research groups, the Internet,and articles in the lay press. This information, as well as informationabout the process of obtaining a genetic test, and the use of genetictest results is discussed with the individual in an ad hoc manner. Manysources of information are written at a level appropriate for healthcarepractitioners. Few are appropriate for individuals in the generalpublic. Moreover, information gleaned from multiple sources is oftenconflicting and incomplete. Few sources of information are validated inclinical studies to demonstrate that the content and mode ofpresentation results in comprehension and retention by the individual.

Documents by which an individual can certify their consent to a genetictest are known in the art. Such documents focus primarily on legalissues related to genetic testing such as the technical and predictivelimitations of genetic testing, potential errors in diagnosis andinterpretation, the disposition of the DNA sample, and the reporting oftest results. Informed consent documents are typically generic, i.e.,they address issues that are relevant to many different genetic testsand clinical outcomes rather than being specific to particular genetictest, genetic tests for related genes, or a specific clinical outcome.

Because of the complexity of genetic information, the widespread lack ofprofessional training in genetics and procedures for delivering geneticservices, and the lack of validated resources for providing geneticservices, surveys suggest that <10% of practitioners feel that they arecapable of adequately providing such services. Moreover, despite laws insome states that require informed consent be obtained before genetictests are performed, data demonstrates that many genetic tests areperformed without any informed consent being obtained or with inadequateinformed consent.

SUMMARY OF THE INVENTION

The inventor has determined that an instrument for obtaining informedconsent comprising integrated elements with information for theindividual, instruction for the practitioner, and materials forcertifying an individual's consent and, optionally, elements forprocessing the genetic record, sample collection, and billing hasutility in assisting practitioners to obtain meaningful and legallybinding informed consent. This instrument may be validated to establishthat it is effective in establishing understanding, comprehension, andeffective use of the test and test result. The instrument described inthis invention provides an individual with information about a genetictest for one gene, more than one gene, related genes, genes associatedwith a clinical outcome or for a gene screen and assists the provider inobtaining a valid informed consent and performing other proceduresassociated with genetic testing.

The instrument comprises an information element, an instruction elementand a certification element. The elements are integrated. Theinformation element contains information sufficient for an individual toprovide a valid informed consent. This element is integrated with aninstructional element for the practitioner that contains more detailedreference information on the gene, gene test, or clinical outcome thatis the subject of the test as well as stepwise directions on how toinstruct the individual in the information in the information elementand materials designed to support such instruction. The integratedinstrument contains both informational materials required by thepractitioner and the individual as well as worksheets, checklists,forms, illustrative materials and other materials required to carry outthese steps in an integrated manner. The information element containsbasic information for individuals about the genetic test including textand illustrative materials in the primary language of the individual andat a level of comprehension appropriate for the general population. Itis generally considered that materials intended for comprehension by thegeneral population should not exceed an 8-10^(th) grade level. Theinformation element is designed to provide individuals with informationthat is accurate, timely, and useful and considered by experts to besufficient for an individual to make an informed decision to proceedwith a genetic test. The information element may contain illustrativematerials as well as supplemental information about genetics, genetictests, or a clinical outcome, or references or links to more advancedinformation available in printed materials or references or links tomore advanced information available in printed materials or electronicmedium.

The instruction element directs the practitioner how to presentinformation to individuals and how to obtain informed consent using theinstrument. This element includes stepwise instructions on the use ofthe instrument and each of the elements comprising the instrument,reference information at the level of the practitioner on medicalgenetics, the genetic test, and related clinical outcomes, and answersto questions that are frequently asked by individuals during the consentprocess. The instruction element preferably contains a checklist todocument that the practitioner has followed each of the steps requiredfor use of the instrument. The instruction element may containillustrative materials for use by the practitioner in presentinginformation to the individual, for example, props, diagrams, worksheets,objects, exercises, questions, or games that can be used to improve theindividuals retention and comprehension of the information. Theinstruction element may also include a worksheet to assist thepractitioner in calculating an individual's genetic risk of a clinicaloutcome based on genetic test results as well as information from theindividual's medical history or family history.

The instruction element advantageously reduces the impact of thepractitioner's subjectivity. It is well known that, for example,validated instruments for neuro-psychological testing require thepractitioner to adhere strictly to the instruction set in order achievevalid testing results. In this invention, the instruction elementprovides the means for standardization of the procedures employed by thepractitioner in obtaining informed consent, and enables consent to beobtained in a validated manner. In addition, it is generally recognizedthat information presented to individuals and the practices of thepractitioner should be non-directive. The standardized and validatedinformation element and instruction elements minimize unintentional biasand improve the quality and ethics of the consent and the consentprocess.

The instrument of this invention also includes a certification element.The certification element comprises a legal document in which theindividual consents to the genetic test before any required witnesses,who certify that the individual has consented to the genetic test.

Optionally included in the instruments of the invention are variousother elements, to with, an assessment element, a collection element, alabeling element, a billing element, a recording element, a trainingelement, a quality control element and an indemnification element. Oneor any more than one of these elements may be included with theinformation, the instruction and the certification elements thatcomprise the instrument of the invention. Preferred elements to beincluded comprise the assessment element or the collection element, orboth. Any optional element included in the instrument is integrated withone or more of the three essential elements.

The assessment element assesses the individual's retention andunderstanding of information contained in the information element andinstruction element. The assessment element comprises questions aboutthe genetic test, the risks and benefits of the test, clinical practiceguidelines, recommendations, and possible clinical actions in responseto the test results. The assessment element is integrated with theinformation element, in that the questions in the assessment elementconcern content from the information element, as well as the instructionelement, which provides correct answers to each of the questions andprocedures for responding to incorrect questions. The assessment elementis intended to determine whether the individual satisfies the minimumstandards of retention and understanding sufficient to provide a validinformed consent. The assessment also serves as an internal form ofquality control on the ability of the practitioner to practice thismethod.

The integrated collection element assists the provider in obtaininginformation from an individual concerning their personal medical historyand family history that is useful in deciding whether or not to have agenetic test performed and quantitatively determine the individual'sgenetic risk. This element is integrated with the information elementwhich describes, for example, how an individual's family history impacttheir risk of a clinical outcome, as well as the instruction elementwhich provides the practitioner with the ability to collect the personalmedical history and family history and analyze this information to makea preliminary assessment of risk.

The other optional elements provide “housekeeping” functions. Thelabeling element and the billing element further assists thepractitioner in processing the sample for genetic testing, establishinga genetic record, and obtaining payment for the test. The recordingelement ensures that a record of the informed consent process and thecertification is established. The training element trains practitionersin the use of the instrument, the quality control element assesses theperformance of the user against performance standards, and theindemnification element provides an indemnification form forpractitioners who use the instrument to obtain consent against claimsthat adequate informed consent was not properly obtained.

The method described in this invention involves the use of an integratedinstrument to obtain valid informed consent. This method comprises,briefly, the steps of transmitting to the individual information on thegenetic test and on the process of testing, instructing the individualwith respect to the genetic test and the testing process and obtainingthe individual's certified consent to the test using an integratedinstrument. The method may optionally include the steps of collecting apersonal medical history and family history using an integratedcollection element, assessing the individual's retention orcomprehension of this information using an integrated assessmentelement, labeling the sample with information required for proper samplehandling using an integrated labeling element, and recording informationconcerning the informed consent process, the test to be performed, andthe individual's medical and family history in a medical record using anintegrated recording element. The method preferably includes the twosteps of collecting and/or assessing. It may include any one or more ofthe remaining steps of labeling, billing training, providing qualitycontrol, indemnification and recording using integrated elements.Preferably these steps are performed using integrated elements.

One or more of the elements of the instrument may be posted to make itgenerally available to individuals or practitioners, by placing it on aweb site, and providing it as a resource in printed or electronic mediumaccessible to individuals or practitioners, or incorporating it inpolicies, practices, guidelines, recommendations, training materials, orlessons and using integrated elements for one or more of the steps ofinforming, instructing, assessing, collecting, certifying, labeling, andrecording. Preferably the information element and/or the instructionelement is posted.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions and GeneralInformation

“Genetic test”, “gene test”, “test”, or “genetic testing” mean theanalysis of DNA, RNA, protein, or other biological materials in a samplefrom an individual to determine, without limitation, the sequence orstructure of one, or more than one, gene, the presence or absence ofone, or more than one, genetic marker, variance, variation, mutation,polymorphism, or micro satellite sequence associated with a gene, thepresence of one, or more than one, viral sequence, viral-like sequence,or repetitive sequence, a haplotype or genotype spanning one, or morethan one, gene, the number of copies of one, or more than one, gene, theamount or characteristics of RNA or protein expressed from one, or morethan one, gene, the biological function of one, or more than one, gene,the arrangement of genes within the genome, the chromosome number, orintegrity, modification, or structure of DNA and chromosomes. Many genetests are useful in medicine for determining and individual's risk of aclinical outcome including diagnosing genetic disease, determining anindividual's propensity to multifactorial diseases, and/or predicting anindividual's response to therapeutic drugs. Genetic tests have beendeveloped for many inherited diseases including, for example,Huntington's Disease, Cystic Fibrosis, and Phenylketonuria. Genetictests have also been developed for genes that predispose to common,multifactorial diseases including, for example, atherosclerosis, heartfailure, stroke, anemia, cancer, clotting disorders, dementia, endocrinediseases, osteoporosis, and pulmonary diseases. Genetic tests have alsobeen described which predict the pharmacokinetic and pharmacodynamiccharacteristics of many drugs including, for example, drugs for thetreatment of elevated cholesterol, drugs to treat cancer, drugs toreduce hypertension, and drugs to treat dementia. The term genetic testincludes any test which determines the structure, characteristics,amount, or activity of certain chemical entities that reflect thestructure or function of one gene or more than one gene.

A common form of a genetic test involves the sequencing of one or moregenes to determine whether the sequence corresponds to a sequence knownto encode a gene product associated with normal biological or clinicalactivity or having a variant sequence that encodes a gene product thatcorrelates with an abnormal function, disease, or clinical outcome. Genesequences can be determined from gels, using automated sequencing, genechips, hybridization to selected or random nucleotide sequences, massspectroscopy or other methods well known in the art. Methods forselectively determining the sequence of one, or more than one, specificbases within a gene or the sequence of a region of a gene known to be amarker for specific health outcomes or to be associated with specificclinical outcomes are also well known in the art. A genetic test mayidentify a single variance within a gene or multiple variances within agene. A genetic test may also identify one or more variances in morethan one gene.

One form of a genetic test is a “gene screen” which identifies a largenumber of variances within one gene or many different genes, potentiallyevery gene in the genome. A gene screen may identify variances in genesthat are related through a common pathway, process, or clinical outcomeand/or genes that are not related. Such tests raise particularlydifficult issues for obtaining informed consent. A specific embodimentof this invention is an instrument for obtaining informed consent for agene screen. Another common form of genetic test well known in the artquantifies the amount or structure of mRNA for one gene or manydifferent genes in a sample. Other forms of genetic tests involveidentification and analysis of specific proteins, or structurallyvariant forms of proteins by mass spectroscopy, electrophoresis, or bybinding to natural or synthetic substrates or antibodies using methodswell known in the art.

“Sample” means an aliquot of material from an individual, for example,blood, tissue, hair, skin cells, mucosal cells, or cells from otherparts of the body, secretions such as saliva, mucous, urine, feces orother bodily tissues, or fluids, useful for genetic testing. Sample alsomeans DNA, RNA, protein or other chemical entities useful for genetictesting that are extracted or purified from such materials. The termrefers to, without limitation, any substance or chemical entity deriveddirectly or indirectly from an individual that contains DNA, RNA,protein, or other materials suitable for performing a genetic test. Asample may contain sufficient material to perform one genetic test or aseries of genetic tests over time. The term “label” is generally knownin the art and refers to information that is attached to or otherwiseassociated with a sample or sample collection device which may containinformation concerning the handling and disposition of the sample, thetest to be performed, and identifying information concerning theindividual.

“Sample collection device” is generally known in the art and includesany device for obtaining samples for genetic tests and placing them in aformat that can be delivered to the site where the sample can beextracted and the test can be performed. Examples of sample collectiondevices for genetic testing are known in the art. Sample collectiondevices may incorporate, for example, filter paper or tubes which holdthe sample for transport to a laboratory, extraction of DNA or othercomponents of the sample, storage of the sample, DNA banking, orperforming one or more steps of the genetic test. It will be recognizedthat several difference devices may be used in the course of obtainingand processing a sample and performing a genetic test and storing thesample, and that multiple labels may be required to transmit informationthrough the course of the sample handling and testing procedures.Samples can be collected using routine procedures for blood drawing andcommonly employ tubes designed to enable the separation of nucleatedcells, plasma or serum. Specialized devices are also known in the artincluding several devices that are approved by the FDA for samplecollection. An exemplary device is the OraSure Oral Specimen CollectionDevice from Orasure Technologies, Inc. which is an FDA-approved devicethat can be used for the collection of DNA from the oral mucosa forclinical applications. Another exemplary device is S&S 903 SpecimenCollection Paper from Schleicher & Schuell, GmbH which is also a FDAlisted device widely used for sample collection, including geneticstudies. S&S 903 Specimen Collection Paper, is used widely for newbornscreening and has also been used for genetic studies. S&S 903 SpecimenCollection Paper has also been incorporated into single and multi-partforms and forms and customized printing is available from themanufacturer with biologically inactive inks and glues that enable thepaper to incorporate information or codes for patient identification,processing, and lot traceability. The 903 device can be used to collectblood or body fluids such as urine, tears, or saliva which are spottedand dried onto the 903 paper. In this form the sample is stable and canbe mailed to centralized labs for analysis, sample extraction, or DNAbanking.

A gene test may be performed using a “diagnostic product” that providesone or more than one of the reagents and materials required to form saidtest and may include a sample collection device. A diagnostic producttypically comprises a kit containing reagents and materials that havebeen subjected to quality control and premeasured so that the test canbe performed effectively by a technician, automated laboratory, or evenan individual. Diagnostic products may be reviewed and approved by theFood and Drug Administration as In Vitro Diagnostics. Most genetictesting today is not performed using approved diagnostics, but ratherperformed under FDA “home brew” guidelines using analyte specificreagents. The term diagnostic product as used herein includes analytespecific reagents, sample collection devices, or other reagents ormaterials used to perform genetic tests.

“Banking” or “DNA banking” means the storage of a sample intended forfuture genetic testing. Since the gene sequences of aggregate somaticcells do not change over time (unless the cells are clonal and/ormalignant), a sample obtained for one genetic test can be banked andadditional tests can be performed at a later time. Informed consent iscommonly required for DNA banking. Such consent must describe thepotential uses of the sample and the final disposition of the sample.Potential uses may include retesting for quality control, genomicresearch, or additional tests for the benefit of the individual that maybe requested by the individual or practitioner. Such consent should alsostate whether a sample will be stored indefinitely or destroyed.Preferably the informed consent for a genetic test includes informedconsent for banking, the permitted uses of the banked sample in thefuture, and the disposition of the banked sample.

“Chemical entity” means proteins, protein derivatives (such asglycoproteins, lipoproteins, or phosphoproteins), lipids, carbohydrates,small-molecule organic compounds, and inorganic compounds measured intissue or body fluids whose structure, activity, characteristics,amount, location, or activity reflects the structure or function of oneor more genes. It is recognized that tests on chemical entities oftenenable direct inferences to be made concerning the structure or activityof one or more genes. For example, electrophoresis of hemoglobinextracted from red blood cells can reveal a change in the hemoglobinmolecule caused by the sickle cell mutation in the hemoglobin gene; anincrease in the amount of phenylalanine in the blood or urine can revealthe presence of mutations in the gene for phenylalanine hydroxylase; theconcentration of salts in sweat can reveal the presence of mutations inthe CFTR gene, the ability of a specific monoclonal antibody tohybridize to a tumor cell may determine whether a genetic rearrangementhas taken place; and a measure of Thiopurine Methyltransferase enzymeactivity may reveal the presence of mutations in the TPMT gene. Oneskilled in the art will recognize that it is frequently more convenientand cost effective to determine the structure or activity of a proteinor to measure metabolites in blood or urine than to perform an analysisdirectly on DNA or RNA. Such tests can be used interchangeably withtests that directly analyze DNA or DNA in the present invention. Manytests can reveal evidence indicating variations in gene sequences,expression or function including, for example, tests for proteins inserum, blood cells, tissues, assays for the expression of specific genesmeasured at the RNA or protein level, and assays for metabolites thatare characteristic of specific gene functions or dysfunctions. It willbe recognized that tests for chemical entities other than DNA or RNA maynot be explicitly included in guidelines or statutes mandating informedconsent. Nevertheless, the information that can be gained from suchtests is often equivalent to that obtained through the analysis of DNAand RNA and presents similar benefits and risks to the individual. Thisinvention specifically relates to tests performed on any chemical entityas a genetic test.

A “gene” is a linear sequence of nucleotides that encode or control abiological function. Genes typically direct the expression of RNA orprotein which may be directly responsible for carrying out the functionencoded by the gene, or the RNA or protein may be subject tomodifications to carry out such functions. The gene may include, withoutlimitation, introns, exons, promoters, or other sequences as well aschemical modifications of the nucleic acids which are involved indetermining a biological function associated with that gene includingthe activity, amount, structure, or location of a chemical entity. Thoseskilled in the art will also recognize that the term gene is also usedto refer to a specific series of nucleotides including characteristicvariations that are associated with a clinical outcome. For example, aCFTR gene with variations that cause cystic fibrosis is often referredto as a “cystic fibrosis gene”, a BRCA1 gene with variations that causebreast cancer is often referred to as a “breast cancer gene”, and aphenylalanine hydroxylase gene with mutations that cause phenylketoniruais referred to as a “PKU gene.”

It is recognized by the skilled artisan that the sequence of nucleotidesin the gene which encode its function may vary in different individuals,and that variances or mutations within the sequences of nucleotides ofthe gene may change its function. The terms “mutation”, “variation”,“polymorphism”, or “variance” refer to sequences within a gene which maydiffer among individuals. The term mutation is typically used todescribe those variations that alter a characteristic activity of a geneor a gene product such as changes in the structure, activity,expression, availability, modification, processing, specificity, orfunction. Mutation more specifically describes those variations thatimpair activity of a gene or a gene product or are associated with anadverse clinical outcome. The terms “genetic marker”, “polymorphism”, or“single nucleotide polymorphism (SNP)”, are typically used to refer tospecific sequences within a gene that can differ among individuals thatare useful as markers to identify specific genes. Use of these termsimplies that the specific variation in sequence does not alter thefunction of the gene, however, such sequences could be associated withcharacteristic activity of the gene or gene product or a specificclinical outcome. When a genetic variation is associated with a specificclinical outcome, the variation, and the gene that contains thatvariation, are said to “cause” or be “linked” or “associated” with thatclinical outcome. Those skilled in the art recognize that a sequencevariance which has detrimental effects in one circumstance, can have noeffect, or even have beneficial effects in other circumstances, thatsequence variances that have biological effects can also be used asmarkers, and that markers may be very closely linked with specificclinical outcomes even if they are not causative. Specific embodimentsof this invention relate to sequence variations that are associated witha specific clinical outcome either because the sequence variation altersthe biological function of a gene in a way that causes the clinicaloutcome, or because the sequence variation is a marker that is linked orassociated with a clinical outcome. The skilled artisan will recognizethat it is often not known whether a specific variance is a mutation ora polymorphism, that the terms “variance”, “variation”, “mutation”,“genetic marker”, “polymorphism”, and “SNP” each refer to differences ingene sequences, or positions in the genome where differences in thesequence are found between different individual, and that these termsare often used interchangeably in describing gene sequences that may bethe object of a genetic test.

Relationships among genes are recognized based on similarities instructure and function, activities that contribute to common biologicalpathways, or activities contributing to a common pathological process orclinical outcome. “Gene family” means genes that share common structuralor functional characteristics or activities. Some genes within a genefamily may exhibit structural similarities due to comparable function(analogy) or evolution (homology) and may contain sequence identities,common motifs, or common functional elements, and may often be locatedin contiguous or closely linked regions of the chromosomes. It isrecognized that genes within a family often carry out analogousbiological functions, and that mutations in closely related genes canlead to similar clinical outcomes. “Pathway” refers to a sequential orintersecting set of biological functions. Several genes and geneproducts are be typically involved in pathways for complex biologicalfunction such as the synthesis of biological compounds, the constructionof cellular or somatic structures, or the regulation of a process withinthe body. It is recognized that genes that contribute to a commonpathway often work in a coordinated fashion, and that variances in anygene along the pathway could alter the characteristic structure, level,or expression of other genes as well as the end product. A disease,disorder or clinical outcome can often involve multiple genes as well asdifferent variances in one or more than one gene. Genes are said to be“related” if they comprise a gene family or are involved in a commonpathway, process, or clinical outcome.

The present invention relates to obtaining informed consent for genetictests for one or more than one variances in one gene or in more than onegene. A preferred aspect of this invention of relates to obtaininginformed consent for genetic tests for more than one gene where suchgenes are related members of a gene family, a pathway, process, orclinical outcome. Obtaining informed consent for such tests may requireproportionally more information on the part of the practitioner andunderstanding on the part of the individual for the consent to be valid.In specific embodiments of this invention, the genetic tests is for twogenes where such genes are related members of a gene family, a pathway,process or clinical outcome, three such genes, five such genes, morethan 5 such genes, more than 10 such genes, or more than 100 such genes.In a specific embodiment of this invention the genetic test is a genethat includes two or more than two genes that may not be related, morethan 10 genes, more than 100 genes, more than 1000 genes, or more than10,000 genes.

“Disease” and “disorder” refer to recognized morbid or pathologicalevents and are commonly catalogued in textbooks of medicine and standardclassifications of disease such as the International Classification ofDisease (ICD). “Clinical outcome” means any observable clinical event orobservation including, for example, disease, disorder, health,morbidity, or mortality; growth, development, aging or longevity; theonset, progression, course, remission, relapse, symptoms, signs, orpathology of a disease or disorder; cognitive function, behavior,psychosis, or dementia; as well as drug response, or drug toxicity orthe response to any intervention involving drugs, nutrition, lifestylechange, education, or surgery as well as the application ofnon-allopathic therapies such as, without limitation, traditional,herbal, or folk medicines, nutricuticals, osteopathy, or chiropracticmedicine. The present invention relates preferably to genetic testsuseful in the field of medicine for predicting a clinical outcome ordetermining the genetic risk of a clinical outcome.

The present invention is applicable to any clinical outcome known in theart for which genetic tests may identify a risk factor for that clinicaloutcome. A skilled artisan would recognize that the present invention isnot limited to diseases that are traditionally identified as beinggenetic in origin but also to clinical outcomes that are“multifactorial”, i.e. associated with combinations of genetic andenvironmental factors. This includes, for example, clinical outcomessuch as heart disease, hypertension, heart failure, coronary vasculardisease, cerebral vascular disease, stroke, peripheral vascular disease,arthritis, rheumatoid arthritis, Lupus Erythematosis (SLE), psoriasis,asthma, reactive airway disease, COPD, osteoarthritis, osteoporosis,hearing loss, cataracts, renal failure, nephritis, hepatic failure,hepatitis, pancreatitis, diabetes, infection, cancer, drug toxicity,drug resistance, drug dependence, neurological diseases, dementia,Alzheimer's disease, psychosis, neuroses, and metabolic diseases.

It is often important to perform genetic tests for multiple variationsthat may occur in one gene, or more than one gene, to determine anindividual's risk of a multifactorial clinical outcome. For example, amutation in one gene may predispose an individual to a high risk of aclinical outcome, which may be increased or decreased by variationsoccurring in another related gene. Many multifactorial diseases are also“polygenic”, meaning that they are associated with variations in morethan one gene. The process of obtaining informed consent for genetictests related to a multifactorial or polygenic clinical outcome isparticularly difficult since it requires the practitioner to instructthe individual in the action of multiple genes singularly and togetheras well as non-genetic or environmental factors that contribute to sucha clinical outcome and how such non-genetic or environmental factors maybe modified to alter the course or incidence of the clinical outcome. Itis recognized that genetic tests are often most useful formultifactorial clinical outcomes since the identification of geneticrisk factors for a clinical outcome may enable modification ofcomplementary non-genetic or environmental risk factors that may alterthe course or incidence of that clinical outcome. In specificembodiments of this invention relate to tests for genes associated withmultifactorial or polygenic clinical outcomes where such outcome isassociated with one gene, two genes where such genes are related membersof a gene family, a pathway, process or clinical outcome, three suchgenes, five such genes, more than five such genes, more than ten suchgenes, or more than 100 such genes. A specific embodiment of thisinvention is an instrument for obtaining informed consent for genetictests one gene, two genes where such genes are related members of a genefamily, a pathway, process or clinical outcome, three such genes, fivesuch genes, more than five such genes, more than ten such genes, or morethan 100 such genes. In a specific embodiment of this invention is aninstrument for obtaining informed consent for a genetic test that is agene screen for two or more than two genes that may not be related,specifically more than 10 genes, more than 100 genes, more than 1000genes, or more than 10,000 genes.

Those skilled in the art recognize that often all of the genes andvariations that are related to a clinical outcome may not yet be known.Genetic tests for variations in known genes are often useful inidentifying risk factors for clinical outcomes. As the number of genesthat are known within the human genome increases as a result of genomicresearch, and as further genomic research ascribes specific functions tothese genes in health and disease and identifies variances within thesegenes that are associated with clinical outcomes, it will be desirableto perform additional genetic tests to further refine the assessment ofrisk. If DNA banking is performed when the initial sample is obtained,it is often possible to use this sample for such additional tests. Aspecific embodiment of this invention is an instrument for obtaininginformed consent for a genetic test for more than one gene, relatedgenes, a clinical outcome, or a gene screen which authorizes DNA bankingand additional genetic tests for related genes at a future time. Inspecific embodiments, informed consent is obtained for such tests withnotification or assent of the individual.

“Genetic risk” is a quantitative and/or statistical measure of thelikelihood that an individual will have a clinical outcome as a resultof variations in one or more than one gene. The risk may be expressed,for example, as the fold increase in risk of a particular clinicaloutcome, the likelihood or probability that an individual willexperience a particular clinical outcome, or an odds ratio. Variousmethods for determining these measures are known by those of ordinaryskill in the art and are commonly described in medical journals inconjunction with the discovery of genes that are considered risk factorsfor specific disease and in textbooks of medicine and genetics. Risk isoften described as a statistical range which describes the probabilityof an individual experiencing a clinical outcome, for example risksbeing <10%, 10-25%, 25-50%, 50-75%, 75-90% or >90%. Risk may also bedetermined as a fold increase in risk, for example and individual mayhave a <2, 2-5, 5-10, or >10 fold increased likelihood of a clinicaloutcome if they have a certain genetic variation. A gene or sequencevariation in a gene is a “risk factor” for a specific clinical outcome,condition and/or disease if the gene or variation is associated with achange in the risk or likelihood of that outcome.

“Genetic risk”, susceptibility”, “predisposition”, and “risk” are oftenused interchangeably to describe the likelihood of a individualexhibiting a disease, disorder, or clinical outcome. It is recognizedthat a risk factor may refer equally to variations that increase therisk of a specific outcome or to variances that reduce the risk of thatoutcome. The determination of genetic risk often makes use of data froma medical and family history in addition to data describing the testresult. The presence or absence of a specific variation or gene may havegreater predictive value based on the family history of a specificclinical outcome and specific pattern of inheritance in that family.

The methods used to determine genetic risk as well as the statisticalsignificance, sensitivity, specificity, and the predictive value of suchinformation is described to the individual as part of the process ofobtaining informed consent. The predictive value of a specific test maybe described as the relative contribution of a specific variance or geneto a clinical outcome or to the fraction of individuals with a clinicaloutcome in which such outcome is attributable to a specific variance orgene. Studies suggest that the perceived accuracy of a test isparticularly important to individuals who are considering whether or notto have a test performed. A description of factors including thetechnical specifications for the test (e.g. false positives and falsenegatives associated with the laboratory procedure), the statisticalsignificance, specificity, and sensitivity of the association between avariance or gene and a clinical outcome, and the predictive value of thetest result all contribute to the perceived accuracy of the test. Whilesuch information is available to those skilled in the art in reportsdescribing the association of a specific variance or gene with aclinical outcome, it is difficult for many practitioners who are notskilled in genetics to ascertain such information and describe thisinformation to individuals. A specific embodiment of this invention isan instrument for obtaining informed consent containing an integratedinstruction element which describes the calculations for determining anindividual risk based on the results of said tests, statisticalprocesses (including the significance, sensitivity, and predictive valueof the test results), personal medical history, and family history. In aspecific embodiment the instrument contains stepwise instructions or aworksheet for the practitioner to determine an individual's risk.

The term “medical history” is well known in the art. The term “familyhistory” or “family medical history” refers to information on the healthof an individual's relatives, diseases they may have suffered, and thecause of death attributed to deceased family members. An individual whoundergoes a genetic test is often referred to as a “proband”. A familyhistory is most commonly obtained by asking an individual about theirrelatives and is commonly presented as a family tree illustrating thefamily relationships and notes about their medical history. A familyhistory may be obtained using computer programs such as TreeBuilder™ orCyrillic™. Certain tests may have limited predictive value in theabsence of a family history of a specific clinical outcome. Other testsmay have greater predictive value if the family history is known. Whengenetic tests are performed for the purpose of reproductive counseling,the family history will also contain information about an individual'sreproductive partner, for example a spouse, partner, or egg or spermdonor, and their related family members.

The term “family members” includes family members of the proband as wellas family members of a reproductive partner. As part of the informedconsent process, it is often important to collect an individual'smedical history and family history to help the individual assess thepotential predictive value of the test. A specific embodiment of thisinvention is an instrument for obtaining informed consent for one, ormore than one, genetic test which includes collection of information onan individual's medical history or family history. A specific embodimentof this invention is an instrument for obtaining informed consent forone, or more than one, genetic test, containing an integrated collectionelement which directs the practitioner how to determine an individual'srisk based on the individual medical history, family history, andresults of said test. In a specific embodiment the instrument containsstepwise instructions or a worksheet for the practitioner to determinean individual's risk based on the medical history or family history. Aspecific embodiment of this invention is a computer program forcollecting an individual's medical history or family history integratedwith an instrument for obtaining informed consent.

Several medical organizations such as the National Institutes of Health,the American College of Human Genetics, and others promulgate“recommendations” on the use of genetic tests that are often based onthe prevalence of a clinical outcome in a specific population ordemographic group or a family history of a clinical outcome. Suchrecommendations are often based on the predictive value of the test andit's potential effects on an individual's quality of life, theprevalence of disease in a population or demographic group and it'spotential impact on health care economics (pharmacoeconomics). Suchrecommendations do not prohibit the use of genetic tests by anindividual, though they may have a role in decisions concerningreimbursement for such tests. An important part of the process ofobtaining informed consent is to instruct an individual concerningrecommendations that are relevant to the test being considered and anassessment of whether the individual meets the criteria for the test andwhether such recommendations are relevant to the individuals concerns. Aspecific embodiment of this invention is an instrument for obtaininginformed consent for a genetic test or more than one genetic test whichdescribes recommendations concerning such tests and guides thepractitioner in an assessment of the recommended course of action forthe individual. A specific embodiment of this invention is an instrumentthat guides the practitioner to instruct individuals concerningrecommendations concerning genetic testing.

An exemplary purpose for performing a genetic test on an individual isto establish an measure of an individual's risk of a specific clinicaloutcome using a genetic test to determine the sequence of one gene, morethan one gene, related or unrelated genes, or a gene screen in thesample, the presence or absence of one, or more than one, sequencevariation genetic marker, variance, variation, mutation, polymorphism,or micro satellite sequence associated with one gene or more than onegenes, the presence of one, or more than one, viral sequence, viral-likesequence, or repetitive sequence, a haplotype or genotype spanning onegene, or more than one gene, related genes, the number of copies of oneor more than one gene, the amount or characteristics of RNA or proteinexpressed from one, or more than one, gene, the biological function ofone, or more than one, gene, the arrangement of genes within the genome,the chromosome number, or integrity of chromosomes.

This invention preferably concerns genetic tests useful in medicine thatidentify associations with a clinical outcome such as a health, geneticdisease, multifactorial diseases, or an individual's response totherapeutic drugs. Such associations are generally established throughclinical trials which collect data both on the clinical outcome andgenetic variations in a sample obtained from the individual. It is oftennecessary to perform multiple clinical trials to achieve a consensus onthe significance of a specific variation on an individual's genetic riskof a specific clinical outcome. Methods for performing such studies areknown to those skilled in the art, and the results of such studies arecommonly reported in publications in the medical literature andpresentations at scientific meetings.

Initial reports of genetic tests may involve studies on smallpopulations which demonstrate the statistical association of a gene orsequence variation with a clinical outcome. Such studies may suggestthat a test has potential utility. These data must then be supplementedby additional studies which confirm and refine the accuracy of thisobservation and establish the utility of the test in quantitativelydetermining the genetic risk of a clinical outcome. Sometimes it isnecessary to perform many studies or perform meta-analyses which combinethe data from several different trials to establish that a test isuseful in determining the genetic risk of a clinical outcome. Studiesperformed as part of the research and development of a genetic test arecommonly described in reports in scientific and medical journals,presentations at scientific meetings, and, sometimes, in filings made toregulatory authorities to obtain authorization for manufacture or saleof a diagnostic product designed for use in performing a genetic test.Once a genetic test has been validated through multiple clinicalstudies, information about such tests will be found in textbooks ofmedicine, genetics or clinical pathology, in materials for medicaleducation and continuing medical education. Once a diagnostic product isapproved by the FDA or offered by a certified testing laboratory,additional information is often available from the manufacturers of adiagnostic product or laboratories that perform the test on a commercialbasis. More than 500 validated tests for variations in specific geneshave been described and are performed by certified laboratories.Information on tests that are commonly performed in clinical practice isavailable to those skilled in the art, for example through the Internetlocations genetest.org and geneclinics.org, textbooks such as Scriver etal., The Molecular Basis of Inherited Disease, McGraw Hill, databasesavailable through the internet location nhgri.nih.gov, the NationalCenter for Biological Information (NCBI) linked to the human genomeproject, and through academic journals of medicine and related sciencesindexed through MEDLINE. New genetic tests are being discovered at arapid rate due to continuing progress of the human genome project andassociated clinical research. Those skilled in the art recognize that itis difficult to remain current on the many reports describing basicgenetic research and clinical trials on genetic tests and theirapplication to determine the genetic risk of many different clinicaloutcomes. Information from such reports is important both to thepractitioner who must describe the test to the individual, and to theindividual who must decide whether or not to have the test performed.Moreover, it is often difficult to describe medical studies in simplelanguage that is generally understandable by individuals. A specificembodiment of this invention is an instrument for obtaining informedconsent for one genetic test or more than one genetic test with anintegrated instruction element which provides the practitioner with acurrent summary of information from reports concerning such test ortests as well as illustrative materials which facilitate the instructionof an individual concerning such tests at an appropriate level ofcomprehension. In a further embodiment this information is incorporatedin an information element for individuals with text and illustrativematerials at a level appropriate for individuals.

The invention provides instruments and methods for obtaining informedconsent comprising validated elements with information concerning thegenetic test, elements for instructing an individual concerning thegenetic test, elements for collection of personal medical history andfamily history, elements for assessing the individual's retention andcomprehension of information, and elements for certification of informedconsent. These methods and instruments enable practitioners andindividuals to obtain a meaningful and legal informed consent.

“Informed consent” or “consent” mean the process by which individualsreceive information about a genetic test, are informed of the potentialbenefits and risks associated with performing a genetic test, andprovide legally binding permission for such a test to be performed ontheir provided sample. The terms informed consent or consent also meanthe legally binding consent provided by an individual or a document, the“informed consent document”, executed by an individual which certifiestheir consent for a genetic test to be performed. “Assent” means theprocess by which an individual indicates their acceptance of a genetictest without providing a legally binding consent. For example, minorsgenerally are considered incapable of providing a legally bindingconsent, but may provide assent. Standards of medical care and somestate laws require that an individual provide an informed consent for agenetic test to be performed.

The elements of a document for certifying individual's consent andguidelines for what constitute an informed consent process and legallybinding informed consent document are known in the art. Informed consentfor genetic testing often resembles the consents obtained for humansubject research as described in the Code of Federal Regulations insections 46.116 and 46.117. These guidelines are formally applicableonly to tests that are performed for research purposes and are notformally applicable to the consents required for validated genetic teststhat are performed for the purpose of determining and individuals riskof a clinical outcome. Nevertheless, many informed consents used forgenetic testing retain the elements of an informed consent for researchpurposes, in part because many genetic tests are not yet fully validatedand may be considered by some to be research even though they areperformed primarily for diagnostic purposes. Also, informed consentstandards for research have been retained for genetic testing becausemany institutions seek consent to use samples and banked DNA that areobtained for diagnostic purposes for research purposes as well. Anembodiment of this invention is an instrument which provides for aninformed consent for genetic in compliance with Code of FederalRegulations in sections 46.116 and 46.117. An exemplary use of suchconsents would be for genetic tests performed for research purposes.

Other informed consents for genetic testing resemble the legal consentsused for medical procedures such as surgery. The principles underlyingsuch consents are primarily matters of state law and legal doctrinearising from common law (judicial decisions) as it applies to decisionsabout medical treatment and procedures. The operable standard under thisdoctrine is that the practitioner must disclose information that is orwould be material to the patient in making his or her decision andinformation that a reasonable practitioner in similar circumstanceswould disclose. Some states in addition to the common law standard havecarved out specific rules (statutes) proscribing the process forinformed consent in regard to specific tests or procedures as well asthe content of the disclosures that must be made to the patient facingthose procedures. In some states genetic testing is treated thisexceptional way and there are specific statutes on genetic testing. Thestatutes in most states are silent on the issue of informed consent forgenetic testing, leaving the common law standard as the one that mustusually be met. In the absence of a legal standard governing informedconsent for genetic testing, the burden is increasingly placed oninstitutions and individual practitioners to provide sufficientinformation and instruction and collect relevant information sufficientto make the consent valid. As described herein, this may include, forexample, information about the genetics, the genetic tests that will beperformed, the use of genetic results, the risks and benefits ofperforming a test, recommendations concerning use of the genetic test,determinations of genetic risk, the use of sample, and procedures forrecords and protecting privacy. The preferred embodiment of thisinvention is an instrument which provides for an informed consent whichassures compliance with statues concerning informed consent for genetictests. An exemplary use of such consent is to obtain consent for a testperformed using a diagnostic product, preferably a diagnostic productapproved by the FDA. Another exemplary use of such consent is to obtainconsent for a test performed by a certified reference laboratoryoperating under CLIA regulations as a “home brew”. A preferredembodiment of this invention is an instrument that provides for aninformed consent for a genetic test that is not research.

The inadequacy of current informed consent practices has been noted inmany reports in the medical literature. Major problems include theinability of many practitioners to provide sufficient information andinstruction for the individual to make a truly informed decision.Another problem is the difficulty of communicating technically difficultinformation at a level appropriate for most individuals. Another problemis the poor retention of information and understanding of informationrequired to provide an informed consent by individuals.

“Individual” means any person who may provide consent for a genetic testor have a genetic test performed. This includes individuals who mayprovide consent for genetic tests performed on their own samples,individuals with legal authority to authorize genetic testing forothers, for example parents who may provide consent for genetic tests ofa minor, and individuals who have tests performed as a consequence ofsuch consent.

“Practitioner”, “provider”, or “health care provider” are usedinterchangeably and include, for example, practitioners specialized ingenetics with MD, PhD or MS degrees, genetic counselors, practitionersof primary care, specialties or subspecialties including physicians,nurses, physicians assistants, pharmacists, social workers,psychologists, as well as other ancillary healthcare professionals ornonprofessional personnel or their designees and the medical practices,hospitals, managed care organizations, or institutions for whom they areagents. The term may also include specialists trained in alternativehealthcare practices including, for example, osteopaths or chiropaths.The terms refer to any provider of health services who may legallyassist an individual in procuring a genetic test. The term practitionermay also relate to automated systems established by, or at the directionof, a practitioner that may be used to obtain informed consent from anindividual. In such instance the term includes computer hardware andsoftware or Internet sites that carry out such functions. In certaininstances the practitioner is a virtual embodiment of the electronicmedium and the instruction element is a computer program that guides theindividual through the process of informed consent in an interactivemanner. In some instances the virtual provider may be represented by aprogram or figure with synthetic voice and voice recognition systems.

“Record” or “recording” refers to a system, document, or file containingmedical data about an individual. The record may contain an individual'sidentity and the results of genetic tests and also information aboutpersonal and developmental history, medical history, family history,clinical laboratory data, images, findings on physical exam, andprevious illnesses and therapies as well as reference or links to otherrecords. Those skilled in the art will recognize that it is important toprotect the privacy of genetic records. Genetic privacy laws in manylocales mandate extensive protections for the privacy of geneticinformation. Methods for protecting the privacy of records are known inthe art and include maintaining records in a secure environment,eliminating identifiable information that can be used to associate anindividual with their record in favor of codes. Patient numbers andpasswords are exemplary codes. A specific embodiment of this inventionis an instrument for obtaining informed consent for a genetic test orone or more genetic tests which incorporates procedures for creating arecord containing genetic information and for protecting the privacy ofsaid record. Those skilled in the art recognize that individuals need tobe informed about policies and procedures used to maintain a recordcontaining the results of a genetic test and any other medicalinformation or identifiable information as part of the process ofproviding informed consent for a genetic test. Individuals must beinformed what steps will be taken to protect privacy, who will beauthorized to access this information, and whether the information maybe used for research purposes. A specific embodiment of this inventionis an instrument for obtaining informed consent for a genetic test orone or more genetic tests which describes procedures with regards to arecord containing genetic information and protections for individualprivacy.

A “test result” or “genetic test result” means the end result of agenetic test including, for example, the sequence of one or more geneswithin a sample, the presence or absence of one or more genetic markers,variances, variations, mutations, polymorphisms, or micro satellitesequences, the presence of one or more viral sequences, viral-likesequence, or repetitive sequence, a haplotype or genotype spanning oneor more genes, the number of copies of one or more genes, the amount orcharacteristics of RNA or protein expressed from one or more genes thebiological function of one or more genes, the arrangement of one or moregenes within the genome, the chromosome number, or integrity ofchromosomes together with known associations of such findings with aspecific clinical outcome. Genetic test results may also includeinferences or statistical data from clinical trials which establish theassociation of test results with a clinical outcome to provide anassessment of genetic risk and may include a determination of geneticrisk based on the genetic test, medical history, family history, andclinical data.

“Genetic counseling” or “counseling” means the process of providinginformation to an individual concerning a genetic test or clinicaloutcome associated with a genetic risk. It includes the process ofproviding information to an individual concerning the use of a genetictest or genetic test result. Counseling is recognized by those skilledin the art to be an essential step in providing an individual with anaccurate assessment of their genetic risk and providing an individualwith assistance in the use of this information in making decisionsregarding healthcare, lifestyle, family planning, reproductivecounseling or other activities. Counseling is generally performed by apractitioner who has specialized training in genetics or in specificdiseases. Counseling generally occurs in a practitioner's office andinvolves one or two sessions with a practitioner. Counseling can beperformed before a test is performed as part of the process of obtaininginformed consent and can also be performed after obtaining the testresults to aid the individual in understanding their genetic risk andmaking effective use of this information.

The process of genetic counseling is described in many articles andtextbooks. The process commonly includes collecting a personal medicalhistory or family history from an individual, discussing the benefitsand risks of a genetic test, communicating the results of a genetictest, and explaining the medical significance of the genetic testresults, elaborating on various health related choices the individualmay make on the basis of the genetic test results, and discussing theconsequences of genetic test results to family members, reproductivepartners, or other individuals designated physician. It is generallyconsidered important for genetic counseling to be “non-directive”,meaning that information is provided to an individual without valuejudgments or implied direction concerning the decision to perform agenetic test and the use of the test results. This is particularlyimportant when genetic tests can be used for reproductive decisions,particularly decisions relating to pregnancy termination. When genetictesting is performed for common diseases, counseling frequently isconcerned with the various treatment options or lifestyle choices.

A critical aspect of genetic counseling is the ability to communicatecomplex information about a clinical outcome, genetic tests, geneticrisk, and genetic test results in a way that it is known to beunderstandable to most individuals. Genetic information is very complex,and it is often difficult to communicate this information to individualswho commonly have little technical background or understanding ofgenetics. Such communications are preferably at the 8^(th) grade levelof written comprehension. In current practice, genetic testing isinitiated by healthcare practitioners. In some instances a prescriptionfrom a practitioner is required for a certified laboratory to perform atest. A specific embodiment of this invention is an instrument forobtaining informed consent for a genetic test or one or more genetictests which also provides a mechanism by which the practitioner canprescribe a genetic test.

A major limitation of current practice is that many healthcarepractitioners, particularly primary healthcare practitioners who are inthe best position to use genetic tests to assess an individuals geneticrisk or predisposition to diseases before they occur, are notsufficiently familiar with the current literature on genetic tests toprovide individuals with information or instruction, collect adequatefamily histories, or obtain a meaningful and legal informed consent.Genetic counseling can be obtained through a referral to a healthcarepractitioner specially trained specially in genetics. The geneticsprofessional commonly meets with the individual one or two times, andthe responsibility for ongoing medical care will continue to reside withthe referring practitioner. It not practical to refer all individuals topractitioners specially trained in genomics. It is anticipated that by2006, 10-40 million tests will be performed annually. At the presenttime there are <3,000 individuals with specialized training in genetics.The instruments described in this invention have utility in providingpractitioners with the information and instructions required to providecounseling to individuals sufficient to obtain an informed consent.

Information about genetic risk is available from sources other thanhealthcare practitioners. Patient support groups specializing in certaindisorders or classes of disorders are often an important source ofinformation for individuals. General information is also available onthe Internet or world wide web, for example at Internet locations suchas genetests.org, geneclinics.org, nih.gov, rarediseases.org,genetichealth.com, dna.com and genesage. While many individuals seekinformation from such sources, the quality and relevance of theinformation varies widely and this information is not integrated withthe counseling provided by the practitioner or the informed consentprocess.

Samples are generally obtained by the health care practitioner, acentral blood drawing service of a hospital or health care clinic, or asatellite facility of a diagnostic testing service. Samples can also beobtained by an individual, for example by using an OraSure device.Samples are commonly sent to genetic testing services, often referred toas reference laboratories for genetic tests, such as Genzyme Genetics,Quest Diagnostics, LabCorp, or Specialty Laboratories, certain clinicallaboratories or hospital based, or academic research laboratories. Suchlaboratories are commonly regulated by Clinical Laboratory ImprovementAct (CLIA) which sets standards for the performance and reporting oftest results. Genetic tests are not currently regulated by the FDAthough, in the future, may be developed as FDA approved diagnostic testsor kits for use by diagnostic laboratories or even home use. Genetictests available from a certified reference laboratory or available asdiagnostic kits are generally referred to as validated, meaning theyhave been subject to clinical evaluations and have demonstrated clinicalutility. Such tests are differentiated from those that are not yetvalidated and are performed on a research basis. A preferred embodimentof this invention relates to validated tests that are not covered byguidelines governing clinical research. A separate embodiment of thisinvention relates to tests that are designed as research where theguidelines for informed consent must comply with sections 46.116 and46.117.

“Validated” is known in the art and refers to the process by which amethod or an instrument is established in a reproducible fashion andsubjected to testing to establish its utility and validity. For example,a clinical procedure or laboratory test is validated if it is performedin a reproducible manner and is shown through research to have clinicalvalue. Methods or instruments are validated through an iterative processof developing the text and materials that comprise the instrument, andthen testing these texts or materials in a clinical study to determinewhether they are understandable. Texts or materials which are poorlyunderstood by study subjects are then revised and retested until adesired level of comprehension is achieved in the study population.Larger studies can then be performed to demonstrate the efficacy of theentire instrument in achieving a desired level of retention andcomprehension in a borad population representing different ethnic,demographic, or socioeconomic groups. Methods for validating aninstrument are known in the art and involve testing the instrument on asufficiently large number of people to perform a statistical analysis onthe data. A set of performance specifications are establish concerningthe retention and understanding of information concerning the genetictest by the individual, the proper handling of the sample and geneticinformation, and the satisfaction of both the individual and thepractitioner in the adequacy of the process. Statistical analysis isperformed to demonstrate that the instrument adequately meets theperformance specifications. In a specific embodiment, the instrumentsdescribed in this invention are validated through clinical studies thatdemonstrate their utility in providing information and counseling toindividuals and obtaining a valid informed consent. Use of a validatedinstrument often involves training in the use of the instrument qualitycontrols designed to maintain consistency in the use of the method orinstrument, as well as quality assessment and process improvementsdesigned to maintain the quality of the method or instrument, and worktowards improvements in efficacy or efficiency.

“Training” means curriculum and materials for instructing practitionersin the use of the instruments and methods described herein. This mayinvolve specialized materials for use in medical education, continuingmedical education, or group or individualized instruction ofpractitioners in the use of the instrument by those skilled in the useof these instruments.

“Quality control” and “quality assessment” refer to the ongoing processof measuring whether performance specifications are being achievedthrough use of the instrument. Quality control is achieved byintegrating elements into the instrument that assess whether theperformance specifications are met and by implementing procedures forreview of these elements on an ongoing basis. Such review may involveanalyzing a random sample of results, results in selected regions orpopulations based on the particular test being performed, the specialtyof the practitioner, or the health, language, ethnic origin, orsocioeconomic status of the individual.

Validated instruments are known in the art, for example, forneurocognitive testing. For examples tests such as the WechslerIndividual Achievement Test (WIAT), Wechsler Adult Intelligence Scale(WAIS), Boehm Test of Basic Concepts, California Verbal Learning(CVLY-II), Kaplan Baycrest Neurocognitive Assessment, Wechsler AdultIntelligence Scale (WAIS-III), Wechsler Intelligence Scale for Children(WISC-III), Bayley Scales of Infant Development (II) and many othertests have been developed to test individuals for neurological,developmental, and psychological performance and achievement. Oncedeveloped these tests are subjected to clinical evaluation to validatethe reliability of the instrument. Practitioners who administer thesetests do so by purchasing packages with the exam that are provided tothe individual taking the test, an instruction set that providesstepwise guidance on performing the test, and a scoring sheet to scorethe individuals answers and compute established performance parameters.Other validated instruments are used to assess clinical depression suchas the Beck Depression Inventory (BDI), Depression Scale (DEPS), DukeAnxiety Depression Scale (DADS), Hopkins System Checklist (HSCL),Primary Care Evaluation of Mental Disorders (PHQ), and the SymptomDriven Diagnostic System-Primary Care (SDDS-PC).

“Integrated” means elements that are linked in their content,components, structure, sale, operation, or use. An instrument isintegrated if it comprises two or more than two integrated elements.Elements are integrated if there is cross-reference between theelements, coordinated text or illustrative materials between theelements, or explicitly complementary functions in the design, content,composition, materials, function, or intended use of the elements. Anexample is an instruction element that guides the practitioner throughthe process of providing information in an information element to anindividual, collecting a medical history or a family history using acollection element, assessing the individual's retention andcomprehension of the information using an assessment element andcertifying their consent using a certification element. Other examplesof integration include providing the practitioner with text orillustrative materials in an instruction element that match orcomplement the information provided directly to the individual in aninformation element, providing the practitioner with instructions, in aninstruction element, for assessing, using an assessment element, anindividual's retention and understanding of the information in theinformation element, and providing the practitioner with materials forobtaining and labeling a sample or sample collection device, creating agenetic record, or billing along with instruction in the use of suchmaterials.

A checklist is a useful component of an integrated instrument.“Checklist” means a form in printed or electronic medium that lists keysteps involved in obtaining an informed consent using the instrumentwhich is designed such that the practitioner can confirm when each stephas been performed and/or completed. The checklist can be used by thepractitioner in practicing the method of obtaining informed consentusing the instrument, can be incorporated in a medical record todocument the method that was used, and can be used for quality controlof the method and instrument. For example, the checklist may listcontain entries related to the description of the genes involved in aclinical outcome, the genetic test, the nature of a specific clinicaloutcome, the role of genetic tests and test results in managing aclinical outcome, how genetic tests are performed, the nature andpurpose of informed consent, how samples are obtained and handled, whathappens to the sample after the test is performed, whether the samplecan be used for other purposes, whether the sample will be available foradditional tests in the future, who will perform the test, who receivesthe test results, what information will be placed in a medical orgenetic record, how this information may be used, policies forprotecting the privacy, as well as other information included in theinformation element or instruction element. A specific embodiment of themethod is use of a checklist for obtaining informed consent using anintegrated instrument.

Worksheets are also useful components of an integrated instrument.“Worksheet” means a form in printed or electronic medium which is usedfor the collection or processing of data. Worksheets are typicallydesigned to prompt the user to collect and record certain data, forexample by filling in the blanks on the form or providing answers tospecific questions. Worksheets can also guide the user through a seriesof calculations by arranging data entries in a convenient layout,providing additional data or data tables necessary for the calculation,and indicating the mathematical functions to be used. Worksheets arerecognized to be useful in obtaining a medical history, review ofsystems, and family history by providing a list of specific symptoms,signs, diseases, or clinical outcomes that should be addressed.Worksheets can be used to calculate genetic risk based on a familyhistory or a genetic test result by providing a format for systematizingthe data, the calculations that need to be performed, and statisticaltables.

The invention provides for the integration of elements for obtaininginformed consent including two, or more than two, or the following: aninformation element, with information for individuals concerning genetictests, an instruction element for practitioners to assist in providinginformation to the individual, obtaining an informed consent, obtaininga sample, and establishing a record, a collection instrument forobtaining an individuals medical history and family medical history, anassessment element to assess the individual's retention andcomprehension of information, a certification element for certifying anindividual informed consent, as well as elements for obtaining andlabeling the sample, creating a genetic record, and billing. A specificembodiment of this invention is the integration of the elements requiredto obtain a valid informed consent into an instrument that may be usedby a practitioner to obtain informed consent from an individual.

Integration is achieved by development of elements designed to be usedin a coordinated fashion. For example, it may first be determined byexperts what information an individual should receive and whatinformation they should retain and understand in order to provide avalid informed consent. An information element for the individual maythen be developed along with an element for assessment that wouldascertain whether an individual retained and understood thisinformation. An instruction element may then be developed as a teachingguide for the practitioner through the process of obtaining consent.These elements may then be subjected to validation to determine whetheruse of the instruction element and information element, in fact,provides most individuals with the requisite information to provideconsent. Several iterations may be required in the development of theseintegrated elements to achieve the performance specifications.Integration is also achieved by providing the practitioner with all ofthe elements required to complete the process of achieving informedconsent, create a medical record, and processing a genetic test.Integration may also be achieved by providing different elementsrequired to obtain informed consent and process a sample together, forexample in the form of a booklet or package that contains severalelements. Integration may also be achieved in the design of the elementssuch that entries made in one element are systematically incorporated inanother element, for example through the use of carbon copies. Suchintegration has utility both in improving the efficiency and quality ofthe informed consent process.

“Electronic medium” are known in the art and the term refers, withoutlimitation, to software and hardware capable of carrying out the uniquemethods and embodiments described herein including the computer code,concept, content, components, design, construction, appearance, look,feel, animation, text, graphics, organization, storage systems,presentation systems, and function of the medium. In an embodiment ofthis invention, the electronic medium are interactive such that theindividual or the practitioner may direct or query the system. In anembodiment of the present invention, such electronic medium containssynthetic speech and speech recognition capabilities.

The terms “printed medium” or “printed materials” are generally known inthe art and refer, without limitation, to text or illustrative materialson paper in bound or unbound form, boards, labels, transparencies,photographs, or objects as well as the concept, content, components,design, construction, appearance, look, feel, figures, graphics, andorganization of the materials. In a preferred embodiment of thisinvention the instrument comprises elements in printed medium that canbe separated.

“Carbon copy” refers to the imprinting of entries made by a practitioneror individual on multiple pages of the instrument simultaneously, forexample through the use of carbon paper or other paper or materialsdesigned for that purpose. Carbon copy also refers to the copying ofinformation entered into one element through electronic means to otherintegrated elements within the instrument, for example by copying intoanother element in electronic medium or through the printing into aprinted medium. In a preferred embodiment of this invention, the printedmaterials are constructed such that a carbon copy of information entriesin one element are copied on other integrated elements.

“Text” is known in the art and means written materials whether inprinted or electronic form including associated images, diagrams, orpictures. “Illustrative materials” means materials designed to assistthe instruction of the individual and promote understanding andretention of the information. Illustrative materials may include,without limitation, diagrams, pictures, photographs, poster, displays,exercises, models, objects, games, props, or worksheets. Illustrativematerials may be in the form of printed medium or electronic medium andmay include various objects. For example, diagrams showing differentpatterns of inheritance may aid the understanding of the role ofinheritance of a particular gene or the inheritance of clinical outcome.Photographs or models may aid the understanding of a clinical outcome.Exercises, games, or worksheets may aid the comprehension and retentionof information. An “object” may be used to illustrate principles ofgenetics, for example the use of dice to illustrate principles of chanceand probability.

This invention comprises printed materials with text and illustrativematerials for carrying out the unique methods and embodiments describedherein. Preferably, the invention is in the form of a booklet withprinted materials comprising each of the elements bound in such a waythat the elements are integrated. For example, a checklist within theinstruction element can be used by the practitioner and thenincorporated in the recording element, answers to questions in theassessment element or the certification on the certification element canbe marked by the individual and incorporated in the recording element,and information in the labeling element and billing element can beincorporated in the recording element. Preferably this is achievedthrough the design of the instrument such that a carbon copy of entriesin one or more elements is also made in the recording element when theinitial entry is made in the other elements of the booklet. Preferablyalso the invention is in the form of a booklet with printed materialscomprising two or more elements bound in such a way that the elementscan be separated. For example, the information element may be separatedand provided to the individual, various illustrative materials may beseparated for use in instruction of the individual, the recordingelement can be separated for incorporation in an individual's generalmedical record, the label element may be separated and affixed to asample collection device, and the billing element may be separated forprocessing by a billing office. This is achieved through the design ofthe instrument using methods known in the art such that pages are boundtogether with certain pages perforated so as to enable easy separationof selected pages from the other pages of the instrument, or certainpages are affixed by adhesives which provide for clean separation of oneor more pages from the instrument. For example, the information elementmay comprise a booklet that can be provided to the individual andretained for their information. For example, elements for assessment,certification, records, labeling, and billing, may comprise separatepages that can be separated from the instrument, and illustrativematerials may be separated for display on a board. In one embodiment,the pages or printing of different elements within the instrument arecolor coded for efficient separation. In alternative embodiment, thedifferent elements are distinguished by size of the page for efficientseparation. The instrument may be a kit containing different printedmaterials including text, illustrative materials or objects in a singlepackage that can be separated for use by the individual andpractitioner.

Alternatively, this invention comprises electronic medium capable ofcarrying out the unique methods and embodiments described herein. Thisis achieved through the design and development of computer programswherein the different elements are presented to the individual orpractitioner as different pages on a computer screen, windows, or pagesprinted by the computer program. Preferably, the elements are integratedthrough the use of a menu or, more preferably, links between theelements. The elements are also preferably linked by the copying ofinformation entered into one element into one or more integratedelements. For example, the information element may be linked to theassessment element so that the individual can answer questions about theinformation which is provided and return to review the information ifnecessary. The instrument may be accessible via the Internet or loadedon a specific computer. Methods are well known to those in the art forconstructing such functioning systems using HTML or JAVA.

The instrument may contain elements comprising printed materials andelements comprising electronic medium. For example, the informationelement may be an audio tape, video tape or interactive computer system,while the elements for certification, labeling, or records are printedmaterials. Alternatively, the information element may be a pamphlet,while other elements of the instrument are in electronic medium.Preferably, the electronic medium is designed such that certain elementscan be printed from the program. For example, the information elementmay be printed for the individual's records and the recording element,labeling element, or billing element can be printed for use by thepractitioner.

The elements of the invention may be in any language, for example,English, Spanish, French, German, Italian, Russian, Japanese, Chinese,or Hebrew. Preferred are elements which use the primary language of theindividual. When the primary language of the individual is differentthan the primary language of the practitioner, certain elements may bein the language of the individual and other elements in the language ofthe practitioner. For example, the information element, collectionelement, assessment element, and certification element may be in theprimary language of the individual, while the instruction element,assessment element, recording element, billing element are in theprimary language of the practitioner. In further embodiments, theinstrument integrates translations for the practitioner of elements thatare in the primary language of the individual within the element. One ormore of the elements of the instrument or components thereof may be inBraille or in oral form (e.g. audiotape, videotape, or electronicsystems with synthetic or recorded voices) for those who are visuallyimpaired or otherwise unable to read printed materials.

B. Detailed Description of the Elements

This invention describes integrated instruments and methods with utilityin obtaining informed consent for genetic tests. The instrumentsdescribed in this invention comprise the following integrated elements:

-   (a) an information element for an individual concerning a genetic    test for one gene, more than one gene, related genes, a clinical    outcome or a gene screen;-   (b) an instruction element for the practitioner useful in providing    instruction to the individual and guidance in the use of the    instrument and obtaining informed consent; and-   (c) a certification element, which can be used to certify the    individual's consent for the test.

The instrument of the invention may optionally include any one or morethan one of the following additional elements:

a collection instrument for collection of information concerning theindividual's personal medical history or their family medical history;

an assessment element for assessment of the individuals retention orcomprehension of the information;

a labeling element for labeling a sample or sample collection devise ordiagnostic used for genetic testing with the identity of the individual;

a billing element for payment by the individual or through areimbursement agency

a recording element that can constitute or be incorporated in anindividual's medical record;

a training element for training the instructor in the use of theinstrument;

a quality control element for monitoring performance of the practitionerand the performance of the instrument; and

an indemnification element that can constitute an agreement to indemnifythe practitioner.

In a preferred embodiment the instrument comprises in an integratedmanner the information, instruction, certification and assessmentelements. In an alternative preferred embodiment the instrumentcomprises in an integrated manner the information, instruction,certification and collection elements. In another preferred embodiment,the instrument comprises in an integrated manner the information,instruction, certification, collection and assessment elements. In yetanother preferred embodiment, the instrument comprises in an integratedmanner the information, instruction, certification, collection andassessment elements and at least one of the elements selected from thegroup consisting of a labeling element, a billing element, a recordingelement, training element, a quality control element, and anindemnification element. Alternatively, the instruments described inthis invention comprises the information, instruction and certificationelements and two, or more than two, or the following: a collectionelement, an assessment element, a labeling element, a billing element, arecording element, a training element, a quality control element, and anindemnification element. More specifically, the instruments described inthis invention may comprise the information, instruction andcertification elements and two, three, four, five, six, seven, or eightof the other elements described herein.

The elements comprising the invention may be integrated individually ina pair wise manner or in groups within the instrument, or, inalternative embodiments of the invention, the instruments may becomprised selectively of such integrated elements. For example, theinformation element may be integrated with one or more of the followingelements: an instruction element, a collection element, an assessmentelement, a certification element, a labeling element, a billing element,a recording element, and a training element. Specifically, theinformation element may be integrated with the instruction element, acertification element, or an assessment element or all three of saidelements. Alternatively, the information element may be integrated withthe instruction element, a certification element, or a training elementor all three of said elements.

In another example, the instruction element may be integrated with oneor more than one of the following elements: an information element, acollection element, an assessment element, a certification element, alabeling element, a billing element, a recording element, and a trainingelement. Specifically, the instruction element may be integrated with acertification or assessment elements. The information and instructionelements may be integrated with one or more than one of the followingelements: an assessment element, a collection element, a certificationelement, a labeling element, a billing element, a recording element, anda training element. Alternatively, the instruction element may beintegrated with an assessment element and one or more than one of thefollowing elements: an information element, a collection element, acertification element, a labeling element, a billing element, arecording element, and a training element. Alternatively, theinstruction element may be integrated with a certification element andone or more than one of the following elements: an information element,a collection element, an assessment element, a labeling element, abilling element, a recording element, or a training element.Specifically, the instrument may contain an instruction elementintegrated with a training element. Alternatively, the instrument maycontain an instruction element integrated with a training element andone or more than one of the following elements: an information element,a collection element, a certification element, an assessment element, alabeling element, a billing element, or a recording element.Specifically, the instrument may contain an instruction elementintegrated with information and assessment elements. Alternatively, theinstrument may contain an instruction element integrated withinformation, assessment, and certification elements. Alternatively, theinstrument may contain an instruction element integrated withcertification and training elements.

In another example, the instrument may contain a certification elementintegrated with one or more than one of the following elements: aninformation element, an instruction element, a collection element, anassessment element, a labeling element, a billing element, a recordingelement, or a training element. Specifically, the instrument may containa certification element integrated with an assessment element.Alternatively, the instrument may contain a certification elementintegrated with an assessment element and one or more than one of thefollowing elements: an instruction element, an information element, acollection element, a certification element, a labeling element, abilling element, a recording element, and a training element.Specifically, the certification element maybe integrated with arecording element. Alternatively, the certification element andrecording element may be integrated with one or more of the followingelements: an information element, an instruction element, a collectionelement, a labeling element, a billing element, and a training element.

In another example, the instrument may contain a training elementintegrated with one or more of the following elements; an informationelement, an instruction element, a collection element, an assessmentelement, a certification element, a labeling element, a billing element,and a recording element. Specifically, the instrument may contain atraining element integrated with an instruction element.

The instrument may be used to obtain informed consent for a genetic testfor one gene. Alternatively, the instrument may be used to obtaininformed consent for a genetic test for more than one gene, relatedgenes or for genes associated with a clinical outcome. The instrumentmay also be used to obtain informed consent for a gene screen test.

The information element comprises text and illustrative materialsintended to provide an individual with sufficient knowledge about agenetic test, the potential medical consequences of a genetic test, andthe procedures involved in genetic testing to provide a meaningful andlegal informed consent. The information element is integrated with oneor more other elements of the instrument. The type of informationrequired for an individual to provide a valid informed consent is knownin the art and disclosed in various textbooks and publications inscientific journals as well as in courses and presentations byindividuals recognized to be opinion leaders in the field. Theinformation element provides such information in the form of text andillustrative materials. The text and illustrative materials includeinformation about a specific clinical outcome, the genes that constituterisk factors for that clinical outcome, the significance of differentgenes that constitute risk factors for that clinical outcome, thepotential actions that could be taken to prevent or treat the clinicaloutcome based on genetic test results, how genetic tests are performed,the purpose of informed consent, the process of obtaining informedconsent, how samples are obtained and handled, the significance andprocess of DNA banking, what happens to the sample after the test isperformed, what happens to banked DNA, whether the sample can be usedfor other purposes, whether the same will be available for additionaltests in the future, who will perform the test, who will receive thetest results, what information will be placed in a medical or geneticrecord, how this information may be used, policies for protecting theprivacy and confidentiality of test results, the availability, natureand role of genetic counseling, factors which should be considered indeciding whether to have a genetic test including the benefits and risksof a genetic test, potential uses of test results in health and wellnessmanagement and lifestyle decisions, the recommendation of professionalorganizations. The information element may also describe in the form oftext and illustrative materials the liabilities of various parties thatmay be involved in providing information, handling the sample,performing the test results, or providing the individual with guidanceon the use of the test results. The information element may also havebackground information about genetics to aid understanding of genetictesting in general, references (for example, books, publications, websites) to more detailed information, and contacts (for example, thenames, telephone numbers or web addresses of organizations orindividuals) who the individual can contact if they wish furtherinformation. In a specific preferred embodiment, the information elementis validated.

The text and illustrative materials are designed for individuals with an8^(th) grade education or level of reading comprehension. Methods forassessing the grade level of language used in such an element are knownin the art. Optionally, the integrated instrument may containinformation elements at different grade levels or links or references toadvanced information for individuals who have the interest and abilityto comprehend such information and the practitioner will select aninformation element with an appropriate level of complexity for theindividual. For example, text and illustrative materials may be providedfor individuals at the 8^(th) grade level, 12^(th) grade level, collegestudents, college graduates, or postgraduate level. Information can beprovided in any language, preferably the primary language of theindividual. Alternatively, information can be provided orally by anaudiotape, videotape, or computer for individuals who may be illiterate.

In a specific embodiment, the text and illustrative materials compriseprinted material. Preferably the text and illustrative materials can bephysically separated from the other elements and provided to theindividual for their review or study. In an alternative embodiment, textand illustrative materials comprise electronic medium. In an embodiment,the instruction element may be a video that provides information to theindividual or an audiotape linked to illustrative materials. In aspecific embodiment, the text and illustrative materials are on theInternet or computer. In another alternative embodiment, the text andillustrative materials are comprised of a combination of printedmaterials, electronic medium, and/or objects.

The instruction element comprises text and illustrative materialsintended to assist a practitioner in the use of the elements thatcomprise the instrument. The text and instructional materials containinstructions for the practitioner on use of the instrument, instructionsfor to be provided by the practitioner to the individual on the use ofthe instrument and the process of providing informed consent,instructional materials to guide discussion with the individualconcerning a genetic test for one gene, more than one gene, relatedgenes, a clinical outcome, or a gene screen, the nature of a specificclinical outcome, and how to prevent or manage a clinical outcomeincluding the role of genetic tests and test results, the genes thatconstitute risk factors for that clinical outcome, the significance ofdifferent genes that constitute risk factors for that clinical outcome,the potential actions that could be taken to prevent or treat theclinical outcome based on genetic test results. The text andillustrative materials also contain instructional materials to guide adiscussion with the individual concerning how genetic tests areperformed, including the nature and purpose of informed consent, howsamples are obtained and handled, what happens to the sample after thetest is performed, whether the sample can be used for other purposes,whether the sample will be available for additional tests in the future,who will perform the test, who receives the test results, whatinformation will be placed in a medical or genetic record, how thisinformation may be used, policies for protecting the privacy andconfidentiality of test results, the availability, nature and role ofgenetic counseling, instruction guiding the individual's choice whetheror not to perform a test, potential uses of test results in health andwellness management and lifestyle decisions, the recommendation ofprofessional organizations, instructions for using the element forassessment including answers to the questions and instructions todetermine whether the individual demonstrates a minimum adequate levelof understanding, instructions for completing informed consent,instructions for obtaining sample, instructions for labeling sample,instructions for completing medical record, additional backgroundinformation on patterns of inheritance, genes, DNA, chromosomes,specific clinical outcomes, psychosocial issues in genetic testing, thepotential for genetic discrimination, and answers to frequently askedquestions. The text and illustrative materials in the instructionelement are integrated with those in the information element in that thetext and illustrative materials in each element may be “overlapping”,i.e., one or more portions of the text and/or illustrative materials inthe instruction element may be quoted in, recapitulated in, or similarin wording or meaning, to a corresponding text and/or illustrativematerial in the information element. The instruction element is intendedfor use by the practitioner in helping individuals understand and retainthe information in the information element. The instruction element canbe in any language, most preferably the primary language of thepractitioner.

The instruction elements also direct the practitioner in how to, interalia, (a) provide information to an individual concerning one or morethan one genetic tests; (b) collect information concerning theindividual's personal medical history or their family medical history;(c) perform an assessment the individual's retention or comprehension ofsaid information; (d) obtain certification of the individual's consentfor said test; (e) obtain a sample for testing; (f) properly label thesample; (g) deliver the sample to the appropriate laboratory for thetest to be performed; (h) bill the individual either directly or througha reimbursement agency and (i) add appropriate information to theindividual's medical record. Preferred embodiments provide theinstructions in a stepwise manner.

In a preferred embodiment, the instruction element contains a checklist,and in an embodiment of the method, the practitioner uses a checklist todocument the steps in obtaining the informed consent. In a preferredembodiment the instruction element contains specific language designedto ensure standardization and quality of the informed consent to be usedby the practitioner to instruct the individual. The checklist containsitems to be discussed with the individual and contains the steps thatcomprise the method for use of the instrument. In a preferred embodimentof the method, the practitioner uses the checklist and integratedelements in obtaining informed consent. In a specific embodiment, theinstruction element is validated.

The text or illustrative materials comprising the instruction elementdescribe the test to be performed, the potential test results, themedical significance of potential test results as well as choices thatan individual may be able to make based on the test results. Theinstruction element may also provide general background informationabout genetics to aid understanding of genetic testing by theindividual. The instruction element may describe specific benefits andrisks of performing the tests and recommendations concerning such theuse of such tests. The text and/or illustrative materials may describethe procedure for obtaining a sample and performing a test, thedisposition and potential future use of the sample as well as the testresults, guidelines for protecting the privacy and confidentiality ofthe individual, procedures for banking DNA, restriction on the use ofbanked DNA, as well as legal boundaries concerning the liability ofvarious parties that may be involved in providing information, handlingthe sample, performing the test results, or providing the individualwith guidance on the use of the test results. The text and/orillustrative materials comprising the instruction element may alsoprovide stepwise direction on how to collect a personal medical historyor a family medical history, preferably using an integrated collectionelement. In a preferred embodiment, the instruction element includestext, methodology and illustrative materials that teach the practitionerhow to use the information collected in the collection element. Morepreferably the instruction element comprises a worksheet that enablesthe practitioner to assess the significance of the personal medicalhistory or family medical history, for example, by calculating the riskof a specific genetic disorder based on the number of affected familymembers. In a preferred embodiment, the instruction element includestext for calculating genetic risks based on the family history. In afurther embodiment, the instruction element may comprise a worksheet orcomputer program that enables a calculation of genetic risk based onfamily history.

In a preferred embodiment in which an assessment element is included inthe instrument, the instruction element directs the practitioner throughan assessment of the individual retention or comprehension. In suchembodiments, the assessment element contains text comprising a series ofquestions to be asked by the practitioner in assessing the individual'sretention or comprehension of the information and a corresponding answerset. In an alternative embodiment, the element for assessment comprisesa series of questions in the form of a questionnaire that can becompleted by the individual, and the instruction element directs thepractitioner in how to administer the questionnaire and provides correctanswers to these questions as well as guidelines for responding tocorrect and incorrect answers.

In a specific embodiment of the present invention, the instructionelement is printed material. In a preferred embodiment the instructionelement can be physically separated from the other elements of theinstrument and retained for use by the practitioner. In an alternativeembodiment the information element is one element of an instrumentcomprising printed materials and electronic medium. For example, theinstruction element may be printed material with directions on the useof a computer program or web site that comprises the information elementor other elements of the instrument. In further embodiments theinformation element is comprised, without limitation, of mixed mediumincluding printed materials, electronic medium, and objects.

In an alternative embodiment, the information element comprises text andillustrative materials in electronic medium_ In a specific embodimentthe instruction element is in electronic medium comprised of text andillustrative materials that are used by the practitioner to instruct thepatient regarding the genetic test and the use of the instrument. In aspecific embodiment the practitioner is a virtual embodiment of theelectronic medium and the instruction element is a computer program thatguides the individual directly through the process of informed consentin a stepwise or interactive manner. For example, the instructionelement may be a computer program to present the individual withinformation using the information element, perform an assessment of theindividual's retention and understanding using the assessment element,create the record using the recording element, provide a label for thesample using the labeling element, and arrange payment using the billingelement. The instruction element in electronic medium may also providethe individual with direction on the appropriate use of one or more ofthe elements, monitor the progress of the individual through theinformed consent process, and provide additional information ordirections as necessary to assist in the effective completion of theinformed consent process and proper processing of the sample. In anembodiment, the instruction element may be a computer program thatinstructs the individual in the use of the instrument. In a specificembodiment, the computer program may integrate the information elementand the instruction element. In an embodiment, the instruction elementin electronic medium may use an animated figure, photographic or videoimage and/or a synthetic voice to represent a practitioner in presentinginformation to the individual and/or instructions on the use of theinstrument. In a specific embodiment the electronic medium employssynthetic voice and voice recognition systems.

The instruction element may contain objects that can be used by thepractitioner in presenting information to the individual. Objects mayinclude models, diagrams, or pictures of the human body or diseasestates, for example, representations of the skeleton, organs or tissues,“Games of chance” such as dice may be useful in explaining thestatistical nature of genetic risk and may be incorporated as objectswithin the instruction element. These objects may be integrated with theinformation element with text or illustrative materials designed todemonstrate genetic principles.

The certification element is a document that can be signed by anindividual to signify their consent for a genetic test to be performed.This document resembles informed consent documents known in the art and,by itself, is designed to comply with any legal or statutoryrequirements for certification of informed consent. The informed consentdocument comprising the certification element summarizes theindividual's understanding of the specific test that will be performed,the benefits and risks involved, the procedure for obtaining a sampleand performing the test, the disposition and potential future use of thesample and the test results, guidelines for protecting the privacy andconfidentiality of the individual and their genetic information, andinformation concerning the liability of parties involved in providinginformation, handling the sample, performing the test, or providing theindividual with guidance on the use of the test results. Thecertification element may also enable the individual to signify theirconsent for DNA banking as well as stated uses of the banked DNA. Thecertification element may also include the individual's consent tospecific forms of follow up, may indicate who should receive the testresults and how they want the results to be reported, may indicatewhether they are interested in receiving information with updates onresearch about the genetic test, the test results, or new tests relatedto a clinical outcome. The document contains blank signature lines forexecution by the individual, the practitioner, and at least one witness.The certification element is integrated with other elements of theinstrument. In preferred embodiments, the certification element isintegrated with the information element and instruction element. Forexample, the certification element may recapitulate essentialinformation from the information element or may incorporate the summaryof instruction provided to the individual or a checklist from theinstruction element. In another preferred embodiment, the certificationelement is integrated with the recording element. In furtherembodiments, the certification element may be integrated with theassessment element, for example by incorporating the results of theassessment. In a specific embodiment, the certification element isvalidated.

The certification element comprises printed material that preferablyincludes multiple execution copies or carbon copies so that duplicatecopes can be retained by the individual and incorporated into themedical record, or provided to others who may require certification ofthe individual's consent. In an alternative embodiment, thecertification element is in electronic form and execution is by alegally recognized electronic signature. In a preferred embodiment, theinstrument is constructed such that the signature entered into thecertification element is directly entered into other elements, forexample the recording element or the labeling element. The certificationelement may additionally include a prescription to be issued by thepractitioner, which authorizes a testing laboratory to perform a test.Such prescriptions for tests are required by certified laboratories incertain states. In a preferred embodiment, certification element isintegrated with the labeling element such that the prescription enteredinto the certification is copied on the label provided to the laboratorywith the sample.

The collection element comprises text and/or illustrative materialsuseful in obtaining an individual's personal medical history or theirfamily medical history. Methods for obtaining personal medical historyare described in basic textbooks and clinical manuals, and tools such asworksheets and computer programs are well known in the art. Such textsand illustrative materials contain questions about past illnesses aswell as a “review of systems” with questions concerning the health ofvarious bodily functions. Standardized instruments and methods forobtaining a family medical history are also known in the art and involvethe cataloguing of information concerning the individual's familymembers, determining their familial relationship to the proband, andrecording their state of health or cause of death. This information istypically portrayed in the form of a family tree. Methods for recordingan individual's medical history and family history are known in the artand may comprise printed materials with worksheets or may compriseelectronic medium in the form of computer programs such as GeneTree ofCyrillic. In the preferred embodiment, the collection element isintegrated with other elements of the instrument. For example, thecollection element may be integrated with the information element suchthat the individual is provided with information about the genetics ofdifferent diseases, disorders, or clinical outcomes that would be usefulin a personal or family history. The collection element may beintegrated with the instruction element such that the practitioner caninstruct the individual in the use of the element and use the data toperform a quantitative assessment of genetic risk. In a specificembodiment, the collection element is validated.

In a further embodiment the collection element may be linked to therecording element to enable follow-up of the proband and family memberswith information regarding the genetic test or test results that may berelevant to clinical outcomes of the proband or family members. Forexample, the collection element may incorporate email, telephone, ormailing addresses of family members or provide the proband withmaterials that can be mailed to these individuals. Information fromthese family members may be incorporated in the collection element toprovide a more complete and accurate collection of the proband's medicaland family history. In a specific embodiment, the collection element isintegrated with the certification element to assure proper authorizationof procedures to contact family members. In a specific environment, thecollection element may be integrated with the certification element andrecording element, enabling the proband and family members to authorizethe distribution of genetic and medical information, receive-follow-up,and release genetic information to their respective medical records

The assessment element comprises a series of questions in the form oftext and illustrative materials that are posed to the individual toassess their retention and comprehension of information. The legalprinciple underlying informed consent for genetic testing is that anindividual must have sufficient comprehension of information to make aninformed choice. The assessment element is designed to determine whetherthe individual has retained and comprehends sufficient informationconcerning the genetic test to provide such a valid informed consent.The assessment element includes text comprising basic questions coveringinformation presented in the information element and instruction elementconcerning a genetic test for one gene, more than one gene, relatedgenes, a clinical outcome or a gene screen to be performed, possibletest results, DNA banking, the medical significance of potential testresults, standard of care recommendations concerning such tests, thechoices available based on the test results, the specific benefits andrisks of performing the tests, the procedure for obtaining a sample andperforming a test, the disposition and potential future use of thesample as well as the test results, guidelines for protecting theprivacy and confidentiality of the individual, and legal issuesregarding liability. The text of the assessment element may incorporatequestions in the form of short answers, multiple choice, true/false,matching, fill in the blank, or other test formats known in the art. Theassessment element is integrated with other elements of the instrument.In a specific embodiment, the assessment element is validated.

In a preferred embodiment, the assessment element comprises printedmaterial in the form of a questionnaire that can be completed by theindividual. In an alternative embodiment, the assessment element is inthe form of interactive electronic medium in which the individual readsand responds to questions on a computer or the Internet. In anotheralternative embodiment, the assessment element is integrated with theinstruction element and the practitioner reads the questions to theindividual and the individual either provides answers on a worksheet orresponds orally and the practitioner records the answers. In a specificembodiment, the assessment element is integrated with the informationelement with provides the individual with sufficient information tocorrectly answer questions in the assessment, is integrated with theinstruction element which provides the practitioner with directions onadministering the assessment and scoring the results, is integrated withthe certification element such that certification can only be providedif the individual exhibits a minimum number of correct answers on theassessment, and integrated with the recording element which incorporatesthe individual's responses to the questions and/or the score on theassessment.

The labeling element comprises materials that are to be attached to asample or a sample collection device to identify the individual, directthe sample to the appropriate laboratory, and designate how the sampleis extracted and banked, and what test is performed. The labelingelement may also designate, either in text, color code, or otherrecognized medium, whether the sample is to be preserved, whether DNA isto be banked, and what uses may be made of the sample. In preferredembodiments, the element comprises one or more than one copy of printedmaterials that form a label that is affixed to the sample or one or moresample collection devices used in the course of obtaining a sample,handling the sample, banking DNA, and performing the genetic test. In aspecific embodiment, the labeling element comprises printed materialswith an adhesive backing that can be separated from the instrument andattached directly to the sample. In alternative embodiments, thelabeling element comprises an electronic medium for generatinginformation required for the label and a method for printing the labelthat can be attached to the sample. In preferred embodiments, thelabeling element is integrated with other elements of the instrument. Ina specific embodiment, the labeling element is validated.

In a specific embodiment of this invention, the instruction elementincludes text and/or illustrative materials directing the practitionerhow to use the labeling element so that the sample is properlycollected, labeled, and directed to the laboratory. In a specificembodiment, the labeling element is integrated with the recordingelement so that there is a record that the sample has been obtained,processed and sent, and the status of the sample, test procedure, andtest results can be tracked. In another specific embodiment, thelabeling element is integrated with the certification element so thatthe laboratory receiving the sample is notified that an informed consenthas been obtained for the specific test and that a prescription has beenprovided by the practitioner.

In a preferred embodiment of this invention the labeling element encodesthe identity of the individual to preserve their privacy andconfidentiality. This may involve attaching a label to the sample thathas personal information encoded or in a form such as a barcode orpersonal identification number that is not readily identifiable exceptto those with appropriate authorization.

The billing element comprises forms required for direct payment by theindividual or forms required to obtain reimbursement or arrange paymentby a third party payor. Such elements are commonly known in the art andmay comprise forms to be completed by the individual and/or thepractitioner with a credit card number, insurance policy number, andbilling codes. Alternatively these forms may comprise electronic mediumor an interactive electronic medium designed to print a form withinformation from the individual or practitioner. In the preferredembodiment the billing element is integrated with other elements of theinstrument.

The recording element comprises materials designed to be placed in anappropriate personal medical records maintained by the practitioner,provided to the individual for their own records, and deposited in otherrecords as may be required, for example, by the practitioner, payor, orregulations The recording element constitutes the legal record of theinformed consent process, providing a record of the procedures used toobtaining the consent, including, for example, information provided tothe individual and any assessment that is performed, documentation ofthe test that is to be performed and any restrictions on the use of theinformation or sample, and certification of the informed consent. Theprocess of maintaining medical records is known in the art and mayinvolve printed materials or electronic medium. In the preferredembodiment, the recording element is integrated with other elements ofthe instrument. In specific embodiments the recording element mayincorporate one or more of the following: a checklist documenting theprocedures for informed consent that were used by the practitioner fromthe instruction element, the personal medical history and family historyof the individual from the collection element, the informed consent andprescription from the certification element, information used to labelthe sample from the labeling element, and information for billing fromthe billing element.

In preferred embodiments, one or more than one of the elements of theinstrument are designed so that information entered into one element isalso incorporated into the recording element in a form suitable forincorporation in the medical record or provided to the individual. In apreferred embodiment these copies comprise printed materials and thedesign of the integrated instrument enables these pages to be physicallyseparated from their respective elements and the complete instrument forinclusion in the record. In alternative embodiments, the instrument isdesigned so that carbon copies of essential information are imprinted onthe recording element, for example, responses or scores from theassessment instrument, the prescription provided by the practitioner, orthe checklist used by the practitioner may be copied directly onto arecording element in carbon copy. Informed consent must be generallycompleted in several copies including one that is given to theindividual and one that becomes part of the individual's record. In aspecific embodiment the recording element incorporates a copy of thecertification element (informed consent document). In an alternativeembodiment, these copies comprise electronic medium that can producematerials for inclusion in the record in either printed material orelectronic medium.

The recording element will commonly contain other information toidentify the individual including a medical record number, informationon the referring practitioner, information on payors, information on thedisposition of the sample, whether DNA has been banked, restrictions onthe use of the sample and banked DNA, restrictions on the use ofpersonal information, and directions on how to contact the individual ortheir practitioner with the test results. State and federal laws setstandards for the protection of genetic information in individualmedical records. The recording element also incorporates codes,mechanisms, procedures, and physical barriers, or fire walls necessaryto protect the privacy of such information. For example, patientinformation may be represented in bar code or personal identifying code,de-identified, or encrypted. Methods and procedures for protecting theprivacy of individual medical records are well known to those skilled inthe art. This invention specifically provides for the individual toprovide necessary releases in the certification element as may berequired by law for the dissemination of information entered into therecording element to practitioners or others authorized by theindividual.

The training element comprises text and illustrative materials designedto train practitioners in the use of the instrument for obtaininginformed consent and methods for obtaining informed consent using saidinstruments. Materials designed for use in medical education andContinuing Medical Education (CME) are known in the art and frequentcomprise printed materials, electronic medium, or mixed medium, forexample, including books, CDs, web sites, pamphlets, slides,presentations. The element may comprise curriculum to be used in medicaleducation or CME as well as illustrative materials that can be used intraining and education. In a preferred embodiment, materials used totrain practitioners in the use of the instrument are integrated with theintegrated with instrument, for example, by describing the compositionor methods of using the instrument, incorporating information, text orillustrative materials from the instrument, diagrams or incorporatingrepresentations of the instrument itself.

The quality control element comprises a reporting form that is used todetermine whether performance specifications are being met by thepractitioner using the instrument in the field. This element containsinformation about the process used to obtain informed consent that canbe used for a review of the performance of the instrument and thepractitioner. A specific utility of this invention is thestandardization and validation of procedures for obtaining informedconsent. There is also provided with this invention a method forperforming quality assessment and quality control of the informedconsent process using the quality control element. This method involvesthe reporting and review of results from the assessment element todetermine whether performance specifications are being achieved in thefield by different practitioners using the instrument in differentpopulations and healthcare settings. The method may involve analysis oftest results from random or selected regions or populations, instrumentsdealing with specific tests, the specialty or subspecialty of thepractitioner, the language of the instrument, or the health, language,ethnic origin, or socioeconomic status of the individual. The results ofsuch analysis can be used to measure the performance of individualpractitioner against performance specifications or to further refine theintegrated instrument, for example through modifications of theinstruction element or modifications of a training element. The qualitycontrol element is integrated with other elements of the instrument. Forexample, the instruction element may inform the practitioner concerningquality control procedures, and the quality control element mayincorporate data from the assessment element and the recording element.

The indemnification element certifies that the methods and instrumentsdescribed in this invention were used to obtain consent and that thesemethods are validated and may provide indemnification against claimsrelated to the adequacy of the informed consent process. The failure toobtain a proper informed consent may render a practitioner liable tolegal action on the part of the individual or government regulatory bodygoverning medical practice claiming that the individual was notadequately informed prior to certifying their consent or a test beingperformed. Use of the integrated and validated instruments and methodsof this invention as described herein is designed to achieve certainperformance specifications and standards including a minimum level ofretention and understanding of information concerning the genetic testby the individual and the effective handling of the sample and geneticinformation.

The indemnification element documents the procedures that were used bythe practitioner to obtain informed consent. The indemnification elementis integrated with other elements of the instrument. For example, theindemnification element may incorporate elements of the informationelement to document the information that was provided to the individual,may incorporate a checklist from the instruction element to documentthat procedure were followed, may incorporate the results of theassessment element to demonstrate that a requisite level of retentionand understanding was observed, and may incorporate the certificationelement to establish that the individual certified their consent. Theindemnification element may be incorporated in the recording element andmaintained with the individual's medical record, or filed with a centralfacility. In a further aspect of this invention, practitioners filing anindemnification element documenting their effective use of theinstrument may receive indemnification against claims related to theadequacy of the informed consent process.

Some exemplary instruments are described below. These are provided forthe purpose of illustrating the invention and are not intended to limitits scope.

Integrated Instruments Containing an Information Element

In a preferred embodiment of this invention, the instrument contains aninformation element integrated with an instruction element and acertification element, and with one or more than one of the following,optionally integrated, elements: a collection element, an assessmentelement, a labeling element, a billing element, a recording element, atraining element, a quality control element and an indemnificationelement. In another embodiment, this instrument contains an integratedinformation element, an integrated instruction element and an integratedcertification element, optionally integrated with two, three, four,five, six, seven or eight of the elements set forth above.

Integrated Instrument Containing an Assessment Element

In a preferred embodiment of this invention, the instrument contains aninstruction element integrated with an information element and acertification element and further contains an optionally integratedassessment element. In another embodiment, this instrument also containsan optionally integrated collection element. In yet another embodiment,this instrument additionally contains one or more than one of thefollowing, optionally integrated elements: a labeling element, a billingelement, a recording element, a training element, a quality controlelement and an indemnification element. In another embodiment, thisinstrument contains an instruction element integrated with aninformation element and a certification element and optionallyintegrated with two, three, four, five, six, seven or eight of theelements set forth above.

Integrated Instrument Containing a Collection Element

In a preferred embodiment of this invention, the instrument contains aninformation element, instruction element and certification element,optionally integrated with a collection element. In another embodiment,this instrument contains in addition one or more than one of thefollowing integrated elements: an assessment element, a labelingelement, a billing element, a recording element, a training element, aquality control element and an indemnification element. In yet anotherembodiment, this instrument contains an integrated information element,integrated instruction element, integrated certification element and anintegrated collection element, optionally integrated with two, three,four, five, six, seven or eight of the elements set forth above.

Integrated Instrument Containing a Collection Element and an AssessmentElement

In a preferred embodiment of this invention, the instrument contains acertification element integrated with an instruction element, with aninformation element and with a collection element and an assessmentelement. Additionally, this embodiment may further include one or morethan one of the following optionally integrated elements: a labelingelement, a billing element, a recording element a training element, aquality control element and an indemnification element. In a specificembodiment of this invention, the instrument contains a certificationelement integrated an instruction element, an information element, acollection element and an assessment element, and optionally integratedwith two, three, four, five, six, or seven of the elements listed above.

Training Element, Quality Control Element, and Indemnification Elements

A preferred embodiment of this invention is an instrument for obtaininginformed consent containing an integrated training element. In suchembodiment, the training element is integrated with the instructionelement, the information element and the certification element. In analternative embodiment, the training element is integrated with thesethree element and with an assessment element or a collection element, orboth assessment and collection elements. In another alternativeembodiment, the training element is integrated with these three elementsand with one or more of the following optionally integrated elements:recording element, labeling element, billing element, quality controlelement, and indemnification element.

A specific object of this invention is an instrument for obtaininginformed consent containing an integrated quality control element. Insuch embodiment, the quality control element is integrated with theinstruction element, the information element and the certificationelement. In an alternative embodiment, the quality control element isintegrated with these three element and with an assessment element or acollection element, or both assessment and collection elements. Inanother alternative embodiment, the quality control element isintegrated with these three elements and with one or more of thefollowing elements: recording element, labeling element, billingelement, training element, and indemnification element. In a preferredembodiment, the quality control element is integrated with these threeelements and with the reporting element. In a preferred embodiment, thequality control element is integrated with these three elements and withthe training element. In further embodiments, the quality controlelement is integrated with two or more than two of the collectionelement, the assessment element, the recording element, the labelingelement, the billing element, the training element and theindemnification element.

A specific object of this invention is an instrument for obtaininginformed consent integrated with an indemnification element. In suchembodiment, the indemnification element is integrated with theinformation element, the instruction element and the certificationelement. In an alternative embodiment, the indemnification element isintegrated with these three elements and an assessment element or acollection element or with both of these elements. A specific embodimentis the integration of the indemnification element with these threeelements and one or more than one of the assessment element, thecollection element, the quality control element, the labeling element,the billing element, the recording element, and the training element. Ina preferred embodiment the indemnification element incorporates achecklist from the instruction element. In a preferred embodiment theindemnification element incorporates the assessment element and thecertification element.

Integrated and Validated Instrument

A preferred embodiment of this invention is a validated instrument forobtaining informed consent comprising the following integrated elements:

(a) an information element for an individual concerning a genetic testfor one gene, more than one gene, related genes, a clinical outcome or agene screen;(b) an instruction element that can be used by a practitioner inproviding instruction to the individual and guidance in the use of theinstrument and obtaining informed consent;(c) a collection element of information concerning the individual'spersonal medical history or their family medical history;(d) an assessment element of the individual's retention or comprehensionof said information;(e) a certification element of the individual's consent for said test;(f) a labeling element for labeling a sample or sample collection deviceobtained for genetic testing with the identity of the individual;(g) a billing element either for direct payment by the individual orthrough a reimbursement agency; and(h) a recording element that can be attached to the individual's medicalrecord.

A specific embodiment of this invention is a validated instrument forobtaining informed consent that contains two or more of the following,optionally integrated, elements, an information element, an instructionelement, a collection element, an assessment element, a certificationelement, a labeling element, a billing element, a recording element, atraining element, a quality control element, and a indemnificationelement. In such embodiments, the instrument contains two, three, four,five, six, seven, eight, nine, or ten of these elements. Anotherspecific embodiment of this invention is a validated instrument forobtaining informed consent that contains an instruction elementintegrated with one or more than one of the following elements: aninformation element, a collection element, an assessment element, acertification element, a labeling element, billing element, a recordingelement, a training element, a quality control element, and aindemnification element. In specific embodiment of this invention, theinstrument contains a instruction element integrated with two, three,four, five, six, seven, eight or nine of said elements.

Integrated Instruments Useful in the Field of Medicine

A preferred embodiment of this invention is an instrument for obtainingconsent for a genetic test for predicting a clinical outcome ordetermining the genetic risk of a clinical outcome, which instrumentcomprises the following integrated elements:

(a) an information element for an individual concerning a genetic testfor one gene, more than one gene, related genes, associated with aclinical outcome;(b) an instruction element that can be used by a practitioner inproviding instruction to the individual and guidance in the use of theinstrument and obtaining informed consent;(c) a collection element of information concerning the individual'spersonal medical history or their family medical history;(d) an assessment element of the individuals retention or comprehensionof said information;(e) a certification element of the individual's consent for said test;(f) a labeling element for labeling a sample or sample collection deviceobtained for genetic testing with the identity of the individual;(g) a billing element either for direct payment by the individual orthrough a reimbursement agency; and(h) a recording element that can be attached to the individual's medicalrecord.

A specific embodiment of this invention is an instrument for obtainingconsent for a genetic test for predicting a clinical outcome ordetermining the genetic risk of a clinical outcome that contains aninstruction element integrated with an information element and with acertification element, and optionally integrated with one or more thanone of the following elements: a collection element, an assessmentelement, a labeling element, a billing element, a recording element, atraining element, a quality control element, and an indemnificationelement. In specific embodiment of this invention, the instrumentcontains the integrated instruction, information and certificationelements optionally integrated with two, three, four, five, six, seven,or eight of the other of the elements listed above.

C. Method of Use

There is provided by this invention a novel method for obtaininginformed consent in which the practitioner uses an integrated instrumentfor obtaining such consent, more specifically a validated instrument. Inspecific embodiments, the method involves the use of an instrument withthe following integrated elements: an information element, aninstruction element, and a certification element, and optionally one ormore elements selected from the group consisting of a collectionelement, an assessment element, a labeling element, a billing element, arecording element, a training element, a quality control element and anindemnification element. The method comprises completing a checklist ofsteps to obtain an informed consent using the instrument and thepractitioner indicates on the checklist the steps that have beenperformed and completed. In a preferred embodiment, the method involvesthe steps of:

-   (a) procuring an integrated instrument for obtaining informed    consent to a genetic test from an individual, which instrument    contains an information element, an instruction element and a    certification element;-   (b) conveying to the individual information concerning the genetic    test using the integrated information element;-   (c) instructing an individual according to the directions contained    in the integrated instruction element; and-   (d) certifying the individual's consent for the test using the    integrated certification element.

In addition, the method may include collecting a personal medicalhistory and family history using an integrated collection element andmay further or additionally include assessing the individual's retentionor comprehension of the information using an integrated assessmentelement. Optionally, the method may further include the steps oflabeling a sample with the identity of the individual using anintegrated labeling element, and recording information concerning theinformed consent process using an integrated recording element.

In a preferred embodiment, the method further includes posting of one ormore elements of an integrated instrument for obtaining informedconsent. Posting makes the element or elements available as a resourceto practitioners in printed or electronic medium (for example, on anInternet site or computer) or by incorporation of the element inpolicies, practices, guidelines, recommendations, training materials, orlessons. The posting of more than one element may be by the same ordifferent means. For example, an instruction element may be posted in aprocedure manual, and information elements provided as booklets to theindividual, and recording elements provided as part of a medical recordsystem. For example, an instruction element from an integratedinstrument for obtaining informed consent may be posted with or withoutany of the additional elements included in the instruments and methodsof the invention.

In detail, the step of “procuring” refers to obtaining an integratedinstrument useful for obtaining informed consent for a specific gene,more than one related gene, a clinical outcome, or a gene screen. Forexample, an instrument may be procured by purchasing the instrument inwritten or electronic form, downloading the instrument from an Internetsite, accessing the instrument on a computer, or printing it from acomputer. Elements of the integrated instrument may be procuredseparately. For example, selected elements may be procured in writtenform, and others downloaded from an Internet site. Procuring also refersto the retrieval of elements that have been posted. Alternatively, oneor more elements may be posted after they are procured by other means.Procuring may involve a payment for the instrument or one or moreelements of the instrument or may be free of charge.

The step of “posting” of an element means to make it generally availableto individuals or practitioners, for example by placing it on a website, providing it as a resource in printed or electronic mediumaccessible to individuals or practitioners. Alternatively, posting mayrefer to policies, business practices, guidelines, recommendations,training materials, lessons that incorporate the use of one or more ofsaid element.

The step of “conveying” refers to the delivery of an information elementto an individual designed to give the individual with backgroundinformation on a genetic test sufficient to provide an informed consent.For example, the individual can be given a booklet containinginformation about the genetic test or provided with access to anInternet site or computer with this information. Preferably conveying isperformed using an information element integrated with one or moreelements of the instrument.

The step of “instructing” refers to giving of instruction to anindividual by a practitioner concerning a genetic test. Preferably,instructing is performed by the practitioner according to directionsincluded in an instruction element integrated with one or more elementsof the instrument.

The step of “collecting” refers to obtaining a personal medical historyand family history from an individual. Preferably, collecting isperformed using a worksheet and instructions included in a collectionelement integrated with one or more elements of the instrument.

The step of “assessing” refers to an assessment of an individual'sretention or comprehension of information sufficient to provide aninformed consent by presenting the individual with questions concerningaspects of the test and testing process and scoring their responses.Preferably assessing is performed using an assessment element integratedwith one or more elements of the instrument element integrated with oneor more elements of the instrument.

The step of “certifying” refers to the completion of a legal informedconsent document by an individual and appropriate witnesses. Preferablycertifying is performed using a certification element integrated withone or more elements of the instrument.

The step of “labeling” refers to the labeling of a sample withinformation required for the proper handling of the sample, performanceof the test, and protection of individual privacy. Preferably, labelingis performed using a labeling element integrated with one or moreelements of the instrument.

The step of “recording” refers to the placement of essential informationconcerning the informed consent process and the individual's medical andfamily history in a medical record. Preferably recording is performedusing a recording element integrated with one or more elements of theinstrument. Indemnifying refers to the issuance of an insurance policywhich pays for claims against the practitioner related to the quality ofthe informed consent obtained using the instrument.

Sample Collection and Diagnostic Devices

An additional embodiment of this invention is kit comprising a samplecollection device and an integrated instrument for obtaining informedconsent for a genetic test. Sample collection devices are known in theart. Samples can be collected using routine procedures from blooddrawing and tubes that enable the separation of white blood cells (thatcontain DNA) from red blood cells, serum, or plasma. Specialized devicesare also known in the art and approved by the FDA for sample collection.The OraSure Oral Specimen Collection Device from Orasure Technologies,Inc. is one example of an FDA-approved sample collection device that canbe used for the collection of DNA from the oral mucosa for clinicalapplications. Another example is S&S 903 Specimen Collection Paper fromSchleicher & Schuell, GmbH is another FDA listed device that is widelyused for adult sample collection, including genetic studies. S&S 903Specimen Collection Paper, is used widely for newborn screening and hasalso been used for genetic studies. S&S 903 Specimen Collection Paperhas also been incorporated into single and multi-part forms and formsand customized printing is available from the manufacturer withbiologically inactive inks and glues that enable the paper toincorporate information or codes for patient identification, processing,and lot traceability. The 903 device can be used to collect blood orbody fluids such as urine, tears, or saliva that are spotted and driedonto the 903 paper. In this form the sample is stable and can be mailedto centralized labs for analysis, sample extraction, or DNA banking.

An additional embodiment of this invention is kit comprising a samplecollection device and an integrated instrument for obtaining informedconsent for a genetic test. In one example, the sample collection deviceis printed S&S 903 paper that is included as part of the labelingelement of the integrated instrument. Alternatively, the samplecollection device may be included in the recording element and may becomprised of a multi-part form comprising S&S 903 paper for samplecollection. In a preferred example, a booklet comprising one or more ofthe elements of the integrated element may contain a page made of S&S903 paper which is perforated or glued to the booklet for easyseparation. The booklet may be constructed such that informationconcerning the individual's identity, the test to be performed, handlingof the sample and test results, and valid certification of consent forDNA banking and testing is entered simultaneously onto a samplecollection device such as S&S 903 paper and onto other elements of theinstrument, for example, by constructing the instrument such that carboncopies are made on one or more elements such as the checklist within theinstruction element, the labeling element, or certification element. Inanother preferred example, sample collection device, for example, S&S903 paper, may be integrated with other elements of the instrument, bydescribing the process for sample collection in the information elementor directions for obtaining and processing a sample in the instructionelement. It will be recognized by those skilled in the art that othersample collection devices may be integrated with the instrument forinformed consent in an analogous manner.

Example 1 Examples of Genetic Tests

A. Genetic Tests Predicting the Risk of Common Disease.

Most common diseases are considered to be multifactorial or polygenic,meaning that many different genes may contribute to the risk of thedisorder. Examples include:

Disorder Genetic test Cancer Breast Cancer (BRCA1)*; BRCA1; OvarianCancer (BRCA1) Breast Cancer (BRCA2)*; BRCA2; Ovarian Cancer (BRCA2)p53, p21, p16 Ataxia Telangectasia NHPCCm FAP (colon cancer) MedullaryThyroid Carcinoma; MTC Alzheimer's Disease Apolipoprotein E amyloidprecursor protein presenilin-1, presenilin-2 2-macroglobulin alpha1-antichymotrypsin Heart attack, stroke Apolipoprotein E Lipoproteinlipase LDL receptor MTHFR Angiotensinogen ALS Superoxide Dismutase (SOD)COPD alpha 1-antitrypsin (AAT) Anemia hemoglobin S hemoglobin Cthalassemia (alpha) thalassemia (beta) G-6 PD Liver failureHemochromatosis Spina Bifida MTHFR Arthritis HLA-B, HLA-D Periodontaldisease IL-1 Osteoporosis Col 1A1

B. Genetic Tests Predictive of Drug Response.

Variations in genes that affect the metabolism of drugs can increasedrug levels, drug toxicity and drug interactions. Genetic tests can beused to avoid drugs that have a higher probability of toxicity andindividualize the dose to maximize the therapeutic benefit whileminimizing toxicity. Examples include:

Gene test Drugs and chemical affected CYP1A1 Chlorinated benzenes(environmental toxin) CYP1A2 Caffeine, phenacetin, warfarin,Erythromycin, Ropivacaine, Haloperidol, antipyrine, theophylline,Paracetamol CYP2C8 TCA, Diazepam, Hexabarbitone CYP2C9/10 Phenytoin,S-warfarin, Diclofenac, Tolbutamide CYP2C19 Mephenytoin, Diazepam(Valium), TCA CYP2D6 Debrisoquine, Codeine, Dextrometorphan, b-blockers,SSRIs, others CYP2E1 Paracetamol, Isoflurane, Sevoflurane,Methoxyflurane, Enflurane, CYP3A4 Nifedipine, Dextrometorphan,Alfentanil, Sufentanil, Fentanyl, Erythromycin, Lignocaine, Ropivacaine,Midazolam, Codeine, Granisetron, Hydrocortisone CYP3A5 Caffeine,Diltiazem CYP3A7 Midazolam CYP17 Pregnolone CYP19 Testosterone CYP21A217-hydroxyprogesterone

C. Variations in Genes that Affect Drug Targets and Drug Response MayAffect the Safety and Efficacy of a Drug.

Genetic tests can be used to avoid drugs that have a higher probabilityof toxicity and individualize the dose to maximize the therapeuticbenefit while minimizing toxicity. Examples include:

Gene test Drugs or chemicals affected Factor V Oral contraceptivesProthrombin Oral contraceptives TPMT (thiopurine Azothioprine,mercaptopurine(purine methyltransferase) analogues) 5′ lipoxegenaseZilutin (5′ lipoxegenase inhibitors) CETP(cholesterol ester Pravastatin,others (statins) transfer protein) ApoE (apolipoprotein E) Tacrine(cholinesterase inhibitors, muscarinic agonists, others) G-6 PD sulfurdrugs Pseudocholinesterase pseudocholinesterase inhibitors Beta-receptorIsoproterenol (beta-agonists) Serotonin transporter SSRI antidepressants(Prozac, Pindolol, others) Acetyltransferase isoniazid, others ADH(2h)(aldehyde alcohol dehydrogenase) ACE (angiotensin Enalpril, othersconverting enzyme Opioid receptors Endorphins, morphine

Genetic Tests for Inherited or Genetic Disorders.

A large number or inherited genetic diseases are caused bywell-characterized mutations in genes that impair the function of a geneor cause a gene to have dominant, adverse effects. The following ispartial list of genetic tests for diseases that are generally consideredto be genetic or congenital.

DiGeorge Syndrome 2

Velocardiofacial Syndrome 2

1p36 Deletion Syndrome 22q11 Deletion Syndrome

Cayler Cardiofacial Syndrome

Conotruncal Anomaly Face Syndrome

DiGeorge Syndrome

Opitz G/BBB

Sedlackova Syndrome

Shprintzen Syndrome

Velocardiofacial Syndrome

3-Methylglutaconic Aciduria 46,XY Gonadal DysgenesisAchalasia-Addisonianism-Alacrima Syndrome Achondrogenesis

Achondrogenesis Type IA Achondrogenesis Type IB

Achondrogenesis Type II

Achondroplasia Acute Hepatic Porphyria Acute Intermittent PorphyriaAdenosine Monophosphate Deaminase 1 Adrenoleukodystrophy, X-Linked

Adrenomyeloneuropathy

Alagille Syndrome Albinism

Ocular Albinism, X-Linked

Oculocutaneous Albinism

Oculocutaneous Albinism Type 1

Oculocutaneous Albinism Type 1A

-   -   Oculocutaneous Albinism Type 1B    -   Oculocutaneous Albinism Type 2 (P Related)    -   Oculocutaneous Albinism Type 3 (TRP1 Related)

Aldosteronism, Sensitive to Dexamethasone Alpha-1-Antitrypsin DeficiencyAlpha-Mannosidosis Alpha-Thalassemia Alpha-Thalassemia X-Linked MentalRetardation Syndrome Alport Syndrome

Alport Syndrome, Autosomal Dominant

Alport Syndrome, Autosomal Recessive

Alport Syndrome, X-Linked

Alzheimer Disease Early Onset Familial Alzheimer Disease

Alzheimer Disease Type 1

Alzheimer Disease Type 3

Alzheimer Disease Type 4

Late-Onset Familial Alzheimer Disease

Alzheimer Disease Type 2

Alzheimer Disease Type 5

Amino Adipic Aciduria Amyotrophic Lateral Sclerosis AndrogenInsensitivity Syndrome

Complete Androgen Insensitivity Syndrome

Mild Androgen Insensitivity Syndrome

Partial Androgen Insensitivity Syndrome

Angelman Syndrome Anhaptoglobinemia Aniridia

An kyloblepharon-Ectodermal Defects-Cleft Lip/Palate

Ankylosing Spondylitis Apolipoprotein E Genotyping ApparentMineralocorticoid Excess Syndrome, Argininemia ArgininosuccinicaciduriaAromatic L-Amino Acid Decarboxylase Deficiency AspartylglycosaminuriaAtelosteogenesis Type II Autoimmune Polyendocrinopathy Syndrome Type 1Autosomal Recessive Adrenoleukodystrophy Autosomal Recessive CongenitalIchthyosis

Congenital Ichthyosiform Erythroderma

Non-Bullous Congenital Ichthyosiform Erythroderma

Avellino Corneal Dystrophy Barth Syndrome Beckwith-Wiedemann SyndromeBeta-Mannosidosis Beta-Methylcrotonylglycinuria Beta-Thalassemia

Thalassemia Intermedia

Thalassemia Major

Thalassemia Minor

Biotin-Responsive Multiple Carboxylase Deficiencies

Biotinidase Deficiency

Holocarboxylase Synthetase Deficiency

Bloom Syndrome Breast Cancer Genetics BRCA1 and BRCA2 HereditaryBreast/Ovarian Cancer

BRCA1 Hereditary Breast/Ovarian Cancer

BRCA2 Hereditary Breast/Ovarian Cancer

Brugada Syndrome CADASIL Camurati-Engelmann Disease Canavan DiseaseCarbamoylphosphate Synthetase I Deficiency Carney Complex CarnitineDeficiency, Systemic

Carnitine Palmitoyltransferase IA (liver) Deficiency

Carnitine Palmitoyltransferase II Deficiency Carnitine-AcylcarnitineTranslocase Deficiency Cartilage-Hair Hypoplasia CatecholaminergicVentricular Tachycardia Catecholaminergic Ventricular Tachycardia,Dominant Catecholaminergic Ventricular Tachycardia, Recessive CeliacDisease Cerebrotendinous Xanthomatosis

Charcot-Marie-Tooth Disease, Type 4B

Charcot-Marie-Tooth Hereditary Neuropathy

Charcot-Marie-Tooth Neuropathy Type 1

Charcot-Marie-Tooth Neuropathy Type 1A

Charcot-Marie-Tooth Neuropathy Type 1B

Dejerine-Sottas Disease

Charcot-Marie-Tooth Neuropathy Type 1C

Charcot-Marie-Tooth Neuropathy Type 1 D

Charcot-Marie-Tooth Neuropathy Type 2

Charcot-Marie-Tooth Disease, Neuronal/Axonal

Charcot-Marie-Tooth Neuropathy Type 2A

Charcot-Marie-Tooth Neuropathy Type 2B

Charcot-Marie-Tooth Neuropathy Type 2C

Charcot-Marie-Tooth Neuropathy Type 2D

Charcot-Marie-Tooth Neuropathy Type 2E

Charcot-Marie-Tooth Neuropathy Type 4

Charcot-Marie-Tooth Neuropathy Type 4A

Charcot-Marie-Tooth Neuropathy Type 4B

Charcot-Marie-Tooth Neuropathy Type 4C

Charcot-Marie-Tooth Neuropathy Type 4D

Charcot-Marie-Tooth Neuropathy Type 4E

Charcot-Marie-Tooth Neuropathy Type 4F

Dejerine-Sottas Disease

Charcot-Marie-Tooth Neuropathy Type X

Hereditary Neuropathy with Liability to Pressure Palsies

CHILD Syndrome Chondrodysplasia Punctata, X-Linked DominantChoroideremia Citrullinemia Clinical Confirmation of MutationsIdentified in Research Labs Cockayne Syndrome

Cockayne Syndrome Type A

Cockayne Syndrome Type B

Cockayne Syndrome Type I

Cockayne Syndrome Type II

Cockayne Syndrome Type III

Xeroderma Pigmentosa-Cockayne Syndrome

Coffin-Lowry Syndrome Congenital Adrenal Hyperplasia

11 beta Hydroxylase Deficiency

17 alpha Hydroxylase Deficiency

21-Hydroxylase Deficiency

3 beta Hydroxysteriod Dehydrogenase Deficiency

Cholesterol Desmolase Deficiency

Congenital Contractural Arachnodactyly Congenital Disorders ofGlycosylation Congenital Erythropoietic Porphyria CongenitalHypomyelination

Congenital Insensitivity to Pain with Anhidrosis

Congenital Muscular Dystrophy

Congenital Muscular Dystrophy with Cerebellar HypoplasiaCongenital Muscular Dystrophy with Early Spine RigidityCongenital Muscular Dystrophy with Integrin alpha 7 MutationsCongenital Muscular Dystrophy with Merosin DeficiencyCongenital Muscular Dystrophy with Mitochondrial StructuralAbnormalities

Congenital Muscular Dystrophy, Merosin-Positive

Fukuyama Muscular Dystrophy

Muscle-Eye-Brain Disease

Walker-Warburg Syndrome

Coronal Synostosis Coronary Artery Disease Risk Factor (ACE) CoronaryArtery Disease Risk Factor (PLA1/2) Craniosynostosis

FGFR-Related Craniosynostosis Syndromes

FGFR1-Related Craniosynostosis SyndromePfeifferSyndrome Type 1, 2, and 3FGFR2-Related Craniosynostosis Syndromes

Apert Syndrome

Beare-Stevenson Syndrome

Crouzon Syndrome

Jackson-Weiss Syndrome

Pfeiffer Syndrome Type 1, 2, and 3

FGFR3-Related Craniosynostosis Syndromes

Crouzon Syndrome with Acanthosis Nigricans

Muenke Syndrome

Cri du Chat Syndrome Cystic Fibrosis

Congenital Bilateral Absence of the Vas Deferens

Cystinosis

Intermediate Cystinosis

Nephropathic Cystinosis

Non-Nephropathic Cystinosis

Cystinuria Cytochrome C Oxidase Deficiency Darier Disease DiabetesMellitus, Noninsulin-Dependent Diabetes Mellitus, Transient NeonatalDiastrophic Dysplasia Disorders of Galactose Metabolism

Galactokinase Deficiency

Galactose Epimerase Deficiency

Galactosemia

Variant Galactosemias Duarte VariGalactosemia Disorders of PhenylalanineMetabolism Phenylalanine Hydroxylase Deficiency

Non-PKU Hyperphenylalanemia

Phenylketonuria

Variant PKU

Tetrahydrobiopterin deficiencies

6-Pyruvoyl-Tetrahydropterin Synthase Deficiency DihydropteridineReductase Deficiency (DHPR)

GTP Cyclohydrolase-1 Deficiency (GTPCH)

Pterin-4a Carbinolamine Dehydratase Deficiency

Tetrahydrobiopterin deficiencies

GTP Cyclohydrolase 1-Deficient DRD

Sepiapterin Reductase Deficiency (SR)

Dopa-Responsive Dystonia

GTP Cyclohydrolase 1-Deficient DRD

Tyrosine Hydroxylase-Deficient DRD

Down Syndrome Critical Region Dubin-Johnson Syndrome Dystrophinopathies

Duchenne/Becker Muscular Dystrophy

-   -   Becker Muscular Dystrophy    -   Duchenne Muscular Dystrophy

X-Linked Dilated Cardiomyopathy

Early-Onset Primary Dystonia Ectrodactyly, Ectodermal Dysplasia, andCleft Lip/Palate Syndrome Ehlers-Danlos Syndrome, Arthrochalasia TypeEhlers-Danlos Syndrome, Kyphoscoliotic Form Ehlers-Danlos Syndrome,Vascular Type Emery-Dreifuss Muscular Dystrophy Epidermolysis BullosaDystrophica, Bart Type Epidermolysis Bullosa Dystrophica,Cockayne-Touraine Type Epidermolysis Bullosa Dystrophica,

Hallopeau-Siemens Type Epidermolysis Bullosa Dystrophica, Inverse Type

Epidermolysis Bullosa Dystrophica, Pasini Type Epidermolysis BullosaJunctional, Disentis Type Epidermolysis Bullosa Junctional,Herlitz-Pearson Type

Epidermolysis Bullosa Letalis with Pyloric Atresia

Epidermolysis Bullosa Simplex

Epidermolysis Bullosa Simplex with Mottled Pigmentation

Epidermolysis Bullosa Simplex, Dowling-Meara Type Epidermolysis BullosaSimplex, Koebner Type Epidermolysis Bullosa Simplex, RecessiveEpidermolysis Bullosa Simplex, Weber-Cockayne Type

Epidermolysis Bullosa with Muscular Dystrophy

Epidermolysis Bullosa, Pretibial Epidermolytic HyperkeratosisEpidermolytic Palmoplantar Keratoderma Erythrokeratodermia VariabilisErythropoietic Protoporphyria Ethylmalonic Encephalopathy Fabry Disease

Cardiac Variant Fabry Disease

Classic Fabry Disease

Facioscapulohumeral Muscular Dystrophy Familial Atypical MycobacteriosisFamilial Colon Cancer Syndromes

Colon Cancer (APC 11307K related)

Familial Adenomatous Polyposis

-   -   Attenuated FAP    -   Gardner Syndrome    -   Turcot Syndrome

Hereditary Non-Polyposis Colon Cancer

Turcot Syndrome

Juvenile Polyposis Syndrome

PTEN Hamartoma Tumor Syndrome (PHTS)

Bannayan-Riley-Ruvalcaba Syndrome

Cowden Syndrome

Proteus Syndrome

Proteus-Like Syndrome

Peutz-Jeghers Syndrome

Familial Combined Hyperlipidemia Familial Dysautonomia FamilialHemiplegic Migraine

Familial Hemiplegic Migraine 1

Familial Hemiplegic Migraine 2

Familial Hibernia Fever Familial Lipoprotein Lipase Deficiency FamilialMalignant Melanoma Familial Mediterranean Fever Fanconi Anemia FarberDisease Fatty Acid Oxidation Disorder, Unspecified Fragile X SyndromeFRAXE Syndrome Frontotemporal Dementia Amyotrophic LateralSclerosis/Frontotemporal Dementia

Frontotemporal Dementia with Parkinsonism-17

Disinhibition-Dementia-Parkinsonism-Amyotrophy

Familial Pick's Disease

Wilhelmsen-Lynch Disease

Progressive Supranuclear Palsy

Fructose 1,6 Bisphosphatase Deficiency Fucosidosis Fumarate HydrataseDeficiency Gaucher Disease

Gaucher Disease Type 1

Gaucher Disease Type 2 (Acute)

Gaucher Disease Type 3 (Subacute/Chronic)

Gaucher Disease, Cardiovascular Form

Gaucher Disease, Perinatal-Lethal Form

Genotypic Gender Assignment Gilbert Syndrome Gliosis, FamilialProgressive Subcortical Glutaricacidemia Type 2 Glycerol KinaseDeficiency Glycogen Storage Disease Type Ia Glycogen Storage DiseaseType Ib Glycogen Storage Disease Type II Glycogen Storage Disease TypeIII Glycogen Storage Disease Type IV Glycogen Storage Disease Type IXGlycogen Storage Disease Type V Glycogen Storage Disease Type VIGlycogen Storage Disease Type VII Glycoprotein 1a Deficiency GM1Gangliosidosis GM2 Gangliosidoses (Hexosaminidase A- and B-Deficient)

Sandhoff Disease

Granular Corneal Dystrophy Greig Cephalopolysyndactyly SyndromeGuanidinoacetate Methyltransferase Deficiency Hailey-Hailey DiseaseHallervorden-Spatz Syndrome Hartnup Disease Hemoglobin C HemoglobinConstant Spring Hemoglobin D Hemoglobin E Hemoglobin O Hemoglobin SHemophilia A Hemophilia B Hereditary Angioneurotic Edema HereditaryAtaxias

Autosomal Dominant Hereditary Ataxias DRPLA

Episodic Ataxia Type 1

Episodic Ataxia Type 2

Spinocerebellar Ataxia Type 1

Spinocerebellar Ataxia Type 2

Spinocerebellar Ataxia Type 3

Spinocerebellar Ataxia Type 4

Spinocerebellar Ataxia Type 5

Spinocerebellar Ataxia Type 6

Spinocerebellar Ataxia Type 7

Spinocerebellar Ataxia Type 8

Spinocerebellar Ataxia TypeI 10

Spinocerebellar Ataxia Type12

Autosomal Recessive Hereditary Ataxias

Ataxia with Oculomotor Apraxia

Ataxia with Oculomotor Apraxia 1

Ataxia with Oculomotor Apraxia 2

Ataxia with Vitamin E Deficiency (AVED)

Ataxia-Telangiectasia

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Friedreich Ataxia

FRDA1 FRDA2

Infantile Onset Spinocerebellar Ataxia (IOSCA)

Marinesco-Sjogren Syndrome

Mitochondrial Disorders with Ataxia

MERF NARP X-Linked Recessive Hereditary Ataxias Sideroblastic Anemia andAtaxia Hereditary Coproporphyria Hereditary Diffuse Gastric CancerHereditary Fructose Intolerance Hereditary Hearing Loss and Deafness

Nonsyndromic Hearing Loss and Deafness

Nonsyndromic Hearing Loss and DeafnessAminoglycoside-Induced DeafnessNonsyndromic Hearing Loss and Deafness, Autosomal Dominant

-   -   DFNA 3 (Connexin 26)    -   Nonsyndromic Hearing Loss and Deafness,    -   Autosomal Recessive

DFNB 1 (Connexin 26)

Nonsyndromic Hearing Loss and Deafness, X-Linked

Syndromic Hearing Loss and Deafness

Mitochondrial Disorders

Diabetes and Hearing Loss

Kearns-Sayre Syndrome

MELAS

MERRF

NARP

Syndromic Hearing Loss and Deafness, Dominant

Alport Syndrome, Autosomal Dominant

Branchiootorenal Syndrome

Neurofibromatosis 2

Stickler Syndrome

-   -   Stickler Syndrome Type I    -   Stickler Syndrome Type II    -   Stickler Syndrome Type III

Waardenburg Syndrome

Waardenburg Syndrome Type I

Waardenburg Syndrome Type II

Waardenburg Syndrome Type III

Waardenburg Syndrome Type IV

Syndromic Hearing Loss and Deafness, Recessive

Alport Syndrome, Autosomal Recessive

Jervell and Lange-Nielsen Syndrome

LQT 1

LQT 5

Pendred Syndrome

Refsum Disease

-   -   Refsum Disease, Adult    -   Refsum Disease, Infantile

Usher Syndrome

-   -   Usher Syndrome Type 1    -   Usher Syndrome Type 2    -   Usher Syndrome Type 3

Syndromic Hearing Loss and Deafness, X-Linked

Alport Syndrome, X-Linked

DFN 1

Norrie Disease

X-Linked Familial Exudative Vitreoretinopathy Hereditary Hemochromatosis

Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia Type 1

Hereditary Hemorrhagic Telangiectasia Type 2

Hereditary Inclusion Body Myopathy 2 Hereditary Multiple Exostoses

Multiple Exostoses Type 1

Multiple Exostoses Type II

Hereditary Pancreatitis Hereditary Sensory and Autonomic Neuropathy IIHereditary Sensory Neuropathy Type I Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegia, Dominant

Hereditary Spastic Paraplegia, Complicated

SPG 9

Hereditary Spastic Paraplegia, Uncomplicated

SPG 3

SPG 4

SPG 6

SPG 8

SPG10

SPG12

SPG13

Hereditary Spastic Paraplegia, Recessive

Hereditary Spastic Paraplegia, Complicated

SPG 7

Hereditary Spastic Paraplegia, Uncomplicated

SPG 5

SPG 11

Hereditary Spastic Paraplegia, X-Linked

Pelizaeus-MerzbacherDisease/Spastic Paraplegia Spastic Paraplegia 1Hermansky-Pudlak Syndrome HPS1

HPS2

HPS3

Hexosaminidase A Deficiency Chronic and Adult-Onset Hexosaminidase ADeficiency

Juvenile (Subacute) Hexosaminidase A Deficiency

Tay-Sachs Disease

Hidrotic Ectodermal Dysplasia 2 Holoprosencephaly NonsyndromicHoloprosencephaly, Autosomal Dominant

Holoprosencephaly 2

Holoprosencephaly 3

Holoprosencephaly 4

Holoprosencephaly 5

Syndromic Holoprosencephaly, Autosomal Dominant

Ectrodactyly and hypertelorism

Martin Syndrome

Pallister-Hall Syndrome

Rubinstein-Taybi Syndrome

Steinfeld syndrome

Syndromic Holoprosencephaly, Autosomal Recessive

Facial clefts and brachial amelia

Genoa Syndrome

Hydrolethalus Syndrome

Lambotte Syndrome

Meckel-Gruber Syndrome

Smith-Lemli-Opitz Syndrome

Homocystinuria Huntington Disease Hydrocephalus, X-Linked Hyper IgDSyndrome Hyperbilirubinemia, Rotor Type HyperekplexiaHyperlipoproteinemia Type III Hyperlysinemia Hyperoxaluria, Primary,Type I Hyperpipecolatemia Hypochondroplasia Hypohidrotic EctodermalDysplasia, Dominant Hypohidrotic Ectodermal Dysplasia, RecessiveHypohidrotic Ectodermal Dysplasia, X-Linked HypophosphatasiaHypophosphatemic Rickets, Dominant Hypophosphatemic Rickets, X-LinkedIchthyosis Bullosa of Siemens Ichthyosis, X-Linked Identity Testing

Parentage Testing

Family Relatedness

Maternity Testing

Paternity Testing

Zygosity Testing

Incontinentia Pigmenti Kallmann Syndrome, X-Linked Krabbe DiseaseLactate Dehydrogenase Deficiency Langer Mesomelic DwarfismLanger-Giedion Syndrome Lattice Corneal Dystrophy Type I LecithinCholesterol Acyltransferase Deficiency Leprechaunism Leri-WeillDyschondrosteosis Lesch-Nyhan Syndrome Li-Fraumeni Syndrome Limb-GirdleMuscular Dystrophy Limb-Girdle Muscular Dystrophies, Autosomal Dominant

Bethlem Myopathy

Caveolinopathy

LGMD1A

LGMD1B

Limb-Girdle Muscular Dystrophies, Autosomal Recessive

Calpainopathy

Dysferlinopathy

Sarcoglycanopathies

-   -   Alpha-Sarcoglycanopathy    -   Beta-Sarcoglycanopathy    -   Delta-Sarcoglycanopathy    -   Gamma-Sarcoglycanopathy

Telethoninopathy

Limb-Mammary Syndrome Lissencephaly Classic Lissencephaly andSubcortical Band Heterotopia (Agyria-Pachygyria-Band Spectrum)

Baraitser-Winter Syndrome

Isolated Lissencephaly/Subcortical Heterotopia

X-Linked Lissencephaly/Subcortical Heterotopia

17-Linked Lissencephaly/Subcortical Heterotopia

Miller-Dieker Syndrome

Cobblestone Dysplasia (Lissencephaly)

Cobblestone Lissencephaly

Muscle-Eye-Brain Disease

Walker-Warburg Syndrome

Lissencephaly Variants with Other Anomalies

Microlissencephaly

Microcephaly with Simplified Gyral Pattern, Group

Microlissencephaly I

Microlissencephaly II

Microlissencephaly III

Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Long ChainAcyl-CoA Dehydrogenase Deficiency Long QT Syndrome

Jervell and Lange-Nielsen Syndrome

LQT 1 LQT 5

Long QT Syndrome, Dominant

LQT 1

LQT 2

LQT 3

LQT 4

LQT 5

LQT 6

Lowe Syndrome Lymphoproliferative Disease, X-Linked MalignantHyperthermia Susceptibility Marfan Syndrome Medium Chain 3-KetothiolaseDeficiency Medium Chain Acyl-Coenzyme A Dehydrogenase Deficiency MenkesDisease Mental Retardation Syndromes, Undiagnosed MetachromaticLeukodystrophy Metaphyseal Chondrodysplasia, Schmid TypeMevalonicaciduria Mitochondrial Disorders

Chorea and Dementia

Chronic Progressive External Ophthalmoplegia

Diabetes and Hearing Loss

Infantile Myopathy and Lactic Acidosis (Fatal and Non-Fatal Forms)

Kearns-Sayre Syndrome

Leber Hereditary Optic Neuropathy

Leigh Syndrome (mtDNA mutation)

MELAS

MERRF

NARP

Nonsyndromic Hearing Loss and Deafness

Aminoglycoside-Induced Deafness

Pearson Syndrome

Molybdenum Cofactor Deficiency MTHFR Deficiency Mucolipidosis IMucolipidosis II Mucolipidosis IV Mucopolysaccharidosis Type IMucopolysaccharidosis Type II Mucopolysaccharidosis Type IIIAMucopolysaccharidosis Type IIIB Mucopolysaccharidosis Type IIICMucopolysaccharidosis Type IIID Mucopolysaccharidosis Type IVAMucopolysaccharidosis Type IVB Mucopolysaccharidosis Type VIMucopolysaccharidosis Type VII Multiple Endocrine Neoplasia Type 1Multiple Endocrine Neoplasia Type 2

Familial Medullary Thyroid Carcinoma

Multiple Endocrine Neoplasia Type 2A

Multiple Endocrine Neoplasia Type 2B

Multiple Epiphyseal Dysplasia Myoclonic Epilepsy of Unverricht andLundborg Myotonia Congenita, Dominant Myotonic Dystrophy

Myotonic Dystrophy Type 1

Myotonic Dystrophy Type 2

Myotubular Myopathies

Myotubular Myopathy, Dominant

Myotubular Myopathy, Recessive

Myotubular Myopathy, X-Linked

Myotubular Myopathy Type 1

Narcolepsy Nephrogenic Diabetes Insipidus

Nephrogenic Diabetes Insipidus, Autosomal

Nephrogenic Diabetes Insipidus, X-Linked

Nephronophthisis

Nephronophthisis, Adolescent

Nephronophthisis, Infantile

Nephronophthisis, Juvenile

Netherton Syndrome Neurofibromatosis 1 Neuronal Ceroid-Lipofuscinoses

Neuronal Ceroid-Lipofuscinosis, Adult

Neuronal Ceroid-Lipofuscinosis, Infantile

Neuronal Ceroid-Lipofuscinosis, Juvenile

Neuronal Ceroid-Lipofuscinosis, Late Infantile

-   -   Neuronal Ceroid-Lipofuscinosis, Late Infantile    -   Neuronal Ceroid-Lipofuscinosis, Finnish Variant    -   Neuronal Ceroid-Lipofuscinosis, Gypsy/Indian,

Early Juvenile Variant

Neuronal Ceroid-Lipofuscinosis, Turkish variant

Northern Epilepsy

Neutrophil Antigen Genotyping Nevoid Basal Cell Carcinoma SyndromeNiemann-Pick Disease Due to Sphingomyelinase Deficiency

Niemann-Pick Disease Type A

Niemann-Pick Disease Type B

Niemann-Pick Disease Type C

Niemann-Pick Disease Type C1

Niemann-Pick Disease, Nova Scotia Type

Niemann-Pick Disease Type C2

Nijmegen Breakage Syndrome Non-Ketotic Hyperglycinemia NonepidermolyticPalmoplantar Hyperkeratosis Noonan Syndrome Oculopharyngeal MuscularDystrophy Organic Acidemias

3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase

Glutaricacidemia Type 1

Isovaleric Acidemia

Ketothiolase Deficiency

Maple Syrup Urine Disease

-   -   Maple Syrup Urine Disease Type 1A    -   Maple Syrup Urine Disease Type 1B    -   Maple Syrup Urine Disease Type 2    -   Methylmalonic Aciduria        Methylmalonic Acidemia cb1C Variant

Propionic Acidemia

Ornithine Transcarbamylase Deficiency Osteogenesis Imperfecta Type IOsteogenesis Imperfecta Type II Osteogenesis Imperfecta Type IIIOsteogenesis Imperfecta Type IV Osteopetrosis, Autosomal Dominant, TypeII Pachyonychia Congenita Paget Disease of Bone PallidopontonigralDegeneration; PPND Papillary Renal Carcinoma Paraganglioma Parkin Typeof Juvenile Parkinson Disease Periodic Paralyses

Hyperkalemic Periodic Paralysis

Hypokalemic Periodic Paralysis

-   -   Hypokalemic Periodic Paralysis Type 1    -   Hypokalemic Periodic Paralysis Type 2

Potassium-Sensitive Cardiodysrhythmic Type Periodic ParalysisPeriodontitis Peroxisomal Bifunctional Enzyme DeficiencyPhosphoglycerate Kinase Deficiency Phosphoglycerate Mutase DeficiencyPhosphorylase Kinase Deficiency of Liver and Muscle Platelet AntigenGenotyping PLOSL Polycystic Kidney Disease

Polycystic Kidney Disease, Autosomal Dominant Polycystic Kidney Disease1, Autosomal Dominant

Polycystic Kidney Disease 2, Autosomal Dominant Polycystic KidneyDisease 3, Autosomal Dominant

Polycystic Kidney Disease, Autosomal Recessive

Porphyria Cutanea Tarda Potocki-Shaffer Syndrome Prader-Willi SyndromePreeclampsia Primary Pulmonary Hypertension Prion Disorders

Creutzfeldt-Jakob Disease

Familial Fatal Insomnia

Gerstmann-Straussler Disease

Progressive Familial Intrahepatic Cholestasis

Progressive Familial Intrahepatic Cholestasis 1

Progressive Familial Intrahepatic Cholestasis 2

PROP 1-Related Combined Pituitary Hormone Deficiency

Proximal Renal Tubular Acidosis with Ocular Abnormalities

Pseudoachondroplasia Pseudoneonatal Adrenoleukodystrophy Pseudovitamin DDeficiency Rickets Pseudoxanthoma Elasticum Pulmonary Surfactant ProteinB Deficiency Pycnodysostosis Pyridoxine-Dependent SeizuresPyruvoyltetrahydropterin Synthase Deficiency Red Cell Antigens

Duffy Antigen Genotyping

Kell Antigen Genotyping

Kidd Genotyping

M Antigen Genotyping

Rh C Genotyping

Rh D Genotyping

Rh E Genotyping

S Antigen Genotyping

Retinitis Pigmentosa

Retinitis Pigmentosa, Autosomal Dominant

Retinitis Pigmentosa, Autosomal Recessive

Retinitis Pigmentosa, Autosomal Recessive, Bothnia Type RetinitisPigmentosa, X-Linked Retinoblastoma Rett Syndrome RhizomelicChondrodysplasia Punctata

Rhizomelic Chondrodysplasia Punctata Type 1

Rhizomelic Chondrodysplasia Punctata Type 2

Rhizomelic Chondrodysplasia Punctata Type 3

Rod Monochromacy Rothmund-Thomson Syndrome Russell-Silver SyndromeSaethre-Chotzen Syndrome Salla Disease Sclerosteosis Sex-DeterminingRegion Y Short Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, ShortChain Acyl-CoA Dehydrogenase Deficiency Short Stature Shox DeficiencySimpson-Golabi-Behmel Syndrome Sitosterolemia Sjogren-Larsson SyndromeSmith-Magenis Syndrome Specialized Cytogenetics Services

Telomere Analysis

X Inactivation Studies

Spinal and Bulbar Muscular Atrophy Spinal Muscular Atrophy

Arthrogryposis multiplex congenita

Congenital axonal neuropathy

Spinal Muscular Atrophy I

Spinal Muscular Atrophy II

Spinal Muscular Atrophy III

Spinal Muscular Atrophy IV

Spinal Muscular Atrophy with Respiratory Distress 1

Split-Hand/Foot Malformation, Type 4 Spondyloepimetaphyseal Dysplasia,Strudwick Type Spondyloepiphyseal Dysplasia Tarda, X-LinkedSteatocystoma Multiplex Succinic Semialdehyde Dehydrogenase DeficiencySulfatidosis, Juvenile, Austin Type Thanatophoric Dysplasia Type IThanatophoric Dysplasia Type II Thrombophilia

Factor V Leiden Thrombophilia

Factor V R2 Mutation Thrombophilia

MTHFR Thermolabile Variant

Prothrombin G20210A Thrombophilia

Thyroid Hormone Resistance Townes-Brocks Syndrome TransthyretinAmyloidosis

Familial Amyloid Cardiomyopathy

Familial Amyloid Polyneuropathy Type I (Portuguese-Swedish-Japanesetype)

Familial Amyloid Polyneuropathy Type II (Indiana/Swiss orMaryland/German type)

Familial Oculoleptomeningeal Amyloidosis

Leptomeningeal Amyloidosis Trichorhinophalangeal Syndrome Type I

Trichothiodystrophy Tuberous Sclerosis Complex

Tuberous Sclerosis I

Tuberous Sclerosis II

Type II Collagenopathies

Achondrogenesis Type II

Kniest Dysplasia

Spondyloepiphyseal Dysplasia

Spondyloepiphyseal Dysplasia, Congenita

Stickler Syndrome Type I

Tyrosinemia Type I Tyrosinemia Type II Uniparental Disomy Testing,General van Buchem Disease Variegate Porphyria Very Long Chain Acyl-CoADehydrogenase Deficiency Vohwinkel Syndrome Von Hippel-Lindau SyndromeVon Willebrand Disease

Von Willebrand Disease Type 2A

Von Willebrand Disease Type 2B

Von Willebrand Disease Type 2M

Von Willebrand Disease Type 2N (Normandy)

White Sponge Nevus of Cannon Williams Syndrome Wilson DiseaseWiskott-Aldrich Syndrome Wolf-Hirschhorn Syndrome Wolman DiseaseX-Linked Adrenal Hypoplasia Congenita X-Linked AgammaglobulinemiaXeroderma Pigmentosa Y Chromosome Deletion

Sertoli Cell Only Syndrome

Y Chromosome Detection/Molecular Genetics

Zellweger syndrome

Zonular Pulverulent Cataract Example 2 Integrated Instrument to ObtainInformed Consent for Genetic Tests for Cystic Fibrosis

Genetic testing for cystic fibrosis is now recommended for all caucasiancouples anticipating childbearing. There are currently ˜4 millionpregnancies/year. Laws in several states require that informed consentbe obtained for all genetic tests. Most primary care physicians andOB/GYNs have little training in genetics and limited ability to provideinformation and instruction to patients concerning genetic tests forcystic fibrosis, the utility and interpretation of test results, theprocedures governing genetic testing and genetic information, thesocial, medical, and psychological implications of testing, and thebalance of risk and benefit involved in having such tests performed. Theinstruments and methods described in this invention enable healthcarepractitioners with little training or knowledge of genetics to obtain ameaningful informed consent using validated and integrated elements forproviding information and instruction to individuals, collecting apersonal medical and family history, assessing the individual'sretention and comprehension of information concerning the genetic test,certifying the individual's consent for the test, establishing a propermedical record, and properly processing the sample.

The integrated instrument contains an instruction element which includesstepwise directions to the practitioner in the process of obtaining aninformed consent and provides text and illustrative materials that thepractitioner can use to explaining the test, the test procedures, andits consequences to the individual. The instrument also contains textand illustrative materials designed for individuals that constitutes areliable and understandable source of information about the test. Acollection element constitutes a worksheet that can be used by thepractitioner and individual to construct a personal medical and familyhistory. The worksheet contains specific questions about theindividual's racial make-up, and the racial make-up of the individualsfamily (siblings, parents, siblings of the parents, grandparents andsiblings of the grandparents, and so on), the individual's health statusand the health status and history of the individual's family. Anassessment element enables the provider to assess the individual'sretention of information. It comprises a series of questions about thereasons for the test, the test procedures, the possible test results andthe meaning of the test results and basic question about cysticfibrosis. The certification element enables the individual to indicatetheir permission for testing to be performed and for this permission tobe witnessed, it includes a written document that states that theindividual has reviewed and understands the information transmitted inthe information element and includes blank signature lines for theindividual's signature, and the signatures of the practitioner and thewitness. Other elements assist in establishing a medical record,labeling the sample, and billing for the cost of the test. Theinstrument is validated through clinical trials which establish that thelanguage comprising the information element and the proceduresestablished in the instruction element are effective in establishing therequisite level of understanding required for an individual to provide avalid informed consent. Table I below sets forth the contents of anexemplary informed consent instrument for Cystic Fibrosis testing.

Example 3 Integrated Instrument to Obtain Informed Consent for GeneticTests for Alzheimer's Disease

Genetic testing for genes involved in Alzheimer's Disease can beperformed for individuals with early symptoms of dementia orasymptomatic individuals with a family history of the disease. WhileAlzheimer's Disease is highly genetic (i.e., it exhibits highheritability) it is also polygenic, meaning many different genes may beinvolved in its etiology. Genetic tests for variances in apolipoproteinE (apoE4) are associated with a more rapid progression of Alzheimer'sdisease, and variations in the genes for amyloid precursor protein,antichymotrypsin, and presenillin have also been associated with thedisease. The genetics of the disease and determinations of risk based onfamily history and genetic test results currently requires specializedtraining in genetics. Most primary care physicians do not have thetraining to instruct patients in the genetics of Alzheimer's Disease,use of genetic information to assess their risk of Alzheimer's Diseasethe social, medical, and psychological implications of testing, and thebalance of risk and benefit involved in having such tests performed.

The instruments and methods described in this invention enablehealthcare practitioners with little training or knowledge of geneticsto obtain a meaningful informed consent using validated and integratedelements for providing information and instruction to individuals,collecting a personal medical and family history, assessing theindividual's retention and comprehension of information concerning thegenetic test, certifying the individual's consent for the test,establishing a proper medical record, and properly processing thesample. These elements comprise a booklet with information aboutAlzheimer's Disease and the role of genetic testing written at an 8^(th)grade level for the patients and give the practitioner stepwisedirections and explicit language to use in explaining the genetics ofAlzheimer's Disease, diagrams illustrating the natural course of earlyand late forms of Alzheimer's Disease and the characteristic patterns ofinheritance of polygenetic disorders, as well as reference informationand answers to frequently asked questions. The instrument also helps thepractitioner collect a family history and provides a worksheet that canbe used to make a quantitative assessment of genetic risk based on thishistory. These elements are validated through clinical trials whichestablish that the language comprising the information element and theprocedures established in the instruction element are effective inestablishing the requisite level of understanding required for anindividual to provide a valid informed consent. Other elements help theprovider to assess the individual's retention of information, enable theindividual to certify their consent, establish a medical record, labelthe sample, and arrange payment for the test. Table II below sets forththe contents of an exemplary informed consent instrument for Alzheimer'sDisease risk.

Example 4 Integrated Instrument to Obtain Informed Consent for GeneticTests for Risk of Stroke

Stroke and other symptomatic manifestations of cardiovascular diseasecan be caused by several different genetic variations. These differentforms of cardiovascular disease may require different therapies. Forexample, variances in apolipoprotein E, LDL, or LDL-R can lead toincreased levels of cholesterol and require therapy with diet and drugsaimed at lowering cholesterol. Variances inmethylenetetrahydro-folatereductase may increase levels of homocysteineand require therapy with diet and folate aimed at lowering cholesterol.Variances in the angiotensinogen gene may lead to cardiovascular diseasedue to imbalances of salt and require therapy with diet, saltrestriction, or diuretics aimed at reducing the salt load. Variances ingenes involved in the clotting cascade, particularly factor V, maypredispose to blood clots and stroke which may be treated withanti-coagulants and anti-thrombotics. Other genetic tests forcardiovascular disease are currently in research and development. Toprovide informed consent for such tests, the practitioner reviews thepatient's family history to make a preliminary calculation of geneticrisk and identify likely candidates for such risk (e.g. history of highcholesterol or thrombosis). Based on this information the practitionermay recommend one for more genetic tests that could be used to customizemeasures to prevent cardiovascular disease and stroke. Most primary carephysicians do not have the sufficient training or knowledge of recentdevelopments in cardiovascular genetics to make such determinations andcounsel patients in the potential use of genetic information in theprevention of cardiovascular disease.

The instruments and methods described in this invention enablehealthcare practitioners with little training or knowledge of geneticsto obtain a meaningful informed consent using validated and integratedelements for providing information and instruction to individuals,collecting a personal medical and family history, assessing theindividual's retention and comprehension of information concerning thegenetic test, certifying the individual's consent for the test,establishing a proper medical record, and properly processing thesample. These elements comprise a booklet with information about thegenetic and non-genetic factors that contribute to stroke written at an8^(th) grade level for the patients and give the practitioner stepwisedirections and explicit language to use in explaining the genetics ofstroke, diagrams illustrating the different factors that contribute tostroke, as well as reference information and answers to frequently askedquestions. The instrument also helps the practitioner collect a familyhistory and provides a worksheet that can be used to make a quantitativeassessment of genetic risk based on this history. These elements arevalidated through clinical trials which establish that the languagecomprising the information element and the procedures established in theinstruction element are effective in establishing the requisite level ofunderstanding required for an individual to provide a valid informedconsent. Other elements help the provider to assess the individual'sretention of information, enable the individual to certify theirconsent, establish a medical record, label the sample, and arrangepayment for the test. The method comprises procuring a booklet thatcomprises the instrument. The information element is separated from thebooklet and given to the patient. The practitioner follows directions inthe instruction element to guide the patient through informationconcerning the ethology of stroke, genetic tests that may be useful inidentifying genetic risk factors for stroke, and the process andconsequences of performing a test. The practitioner uses a check list toindicate the completion of each step of the process. The practitionerthen uses the collection element to collect a personal family andmedical history and a worksheet within this element to make adetermination of the patient's genetic risk. An assessment of thepatient's retention and understanding of the information is made usingthe assessment instrument, and, when an acceptable level ofunderstanding is demonstrated, the patient signs an informed consentform with witnesses from the certification element according todirections in the instruction element. Carbon copies of the checklist,assessment, and certification are made onto a recording elementcoincident with the original signatures, and this element is placed inthe patient's medical record as described in the instruction element.The sample is labeled with an adhesive backed label that is separatedfrom the back cover of the instrument as described in the instructionelement, and the invoice is separated from the instrument and given tothe patient. Table III sets forth the contents of an exemplary informedconsent instrument for genetic risk of stroke.

Example 5 Integrated Instrument to Obtain Informed Consent forPharmagenogenetic Testing

Genetic variation in genes that are responsible for drug metabolism mayalter the safety and efficacy of these medications for an individual.These tests may, for example, identify individuals who are refactory tothe pain-killing effects of codeine, individuals who are at risk fromundue toxicity from various neuro-psychiatric drugs, and individuals whoare at risk of abnormally high levels of warfarin. CYP2D6 and CYP3C9 aretwo examples of genes that may be tested to help guide the choice ofpharmaceutical therapy. Genetic tests for pharmacogenetic testing willcommonly be performed by the prescribing physician who may have littleor no training in genetics and in situations where professional geneticssupport may not be available. While the genetic predisposition toadverse drug events or drug resistance may not raise some of the ethicalissues that surround genetic tests for disease predisposition, informedconsent is, nevertheless, necessary regarding issues such as samplehandling, DNA banking, and the privacy of genetic records. Accordingly,physicians need to have an effective method for providing individualswith information concerning the test, how the test results can be used,and how follow-up may be maintained, instructing the individualconcerning the handling of the sample and information from the genetictest, and obtaining a valid informed consent.

The instruments and methods described in this invention enablehealthcare practitioners with little training or knowledge of geneticsto obtain a meaningful informed consent using validated and integratedelements for providing information and instruction to individuals. Theseelements comprise a booklet with information about genetic effects ondrug action and the process of genetic testing written at an 8^(th)grade level for the patients and give the practitioner stepwisedirections and explicit language to use in explaining how thisinformation could be used to improve the choice of the medication andthe dose that will be prescribed. The instrument also contains anassessment to determine the individual's comprehension and retention ofinformation concerning the test and testing procedures. Theseinformation element and instruction element also contain materialsrelating to a follow-up service through which individuals are contactedwith regular updates concerning new medications and how thesemedications are affected by genetic variations. Individuals are asked toindicate their consent for such contacts by the service or to formallyreject such contacts in the certification element. The choice whether ornot to participate in the follow-up program is also noted in therecording element. If the individual chooses to participate, thiselement will also include contact information for such follow-up andcopies of this element will be recorded automatically with the follow-upservice. The billing element is used to pay both for the genetic teststhat are to be performed and for an initial subscription to thisservice. Also included in the instrument are elements for labeling ofthe sample. Table IV below sets forth the contents of an exemplaryinformed consent instrument for pharmacogenetic testing.

REFERENCES

-   Code Of Federal Regulations—§46.116, 46.117-   Elias S, Annas G J. Generic consent for genetic screening. N Engl J    Med 1994; 330:1611-1613-   Andrews L B, Fullarton J E, Holtsman N A, Motulsky A G, eds.    Assessing genetic risks: implications for health and social policy.    Washington, D.C.: National Academy Press, 1994-   Ciske D J, Haavisto A, Laxova A, Rock L Z, Farrell P M. Genetic    counseling and neonatal screening for cystic fibrosis: an assessment    of the communication process. Pediatrics 2001 April; 107(4):699-705-   Andrews L B., Compromised consent: deficiencies in the consent    process for genetic testing. J Am Med Womens Assoc 1997 Winter;    52(1):39-42-   Hofman K J, Tambor E S, Chase G A, Geller G, Faden R R, Holtzman N    A., Physicians' knowledge of genetics and genetic tests. Acad Med    1993 August; 68(8):625-32-   Cho M K, Arruda M, Holtzman N A., Educational material about genetic    tests: does it provide key information for patients and    practitioners? Am J Med Genet 1997 Dec. 19; 73(3):314-20-   Robertson J A., Consent and privacy in pharmacogenetic testing. Nat    Genet 2001 July; 28(3):207-9-   Geller G, Strauss M, Bernhardt B A, Holtzman N A., “Decoding”    informed consent. Insights from women regarding breast cancer    susceptibility testing. Hastings Cent Rep 1997, March-April;    27(2):28-33-   Rieger P T, Pentz R D., Genetic testing and informed consent. Semin    Oncol Nurs 1999 May; 15(2):104-15-   U.S. Pat. No. 6,149,440 entitled Methods and Apparatus for    Authenticating Informed Consent-   U.S. Pat. No. 5,999,909 entitled Methods for Establishing a    Certifiable Informed Consent For A Procedure-   U.S. Pat. No. 5,799,282 entitled Methods for Establishing    Certifiable Informed Consent For A Medical Procedure

I claim:
 1. An instrument for obtaining from an individual informedconsent to a genetic test, said instrument comprising: (a) aninformation element; (b) an instruction element, integrated with saidinformation element; and (c) a certification element, integrated withsaid instruction and said information elements.
 2. An instrumentaccording to claim 1 wherein said genetic test is selected from thegroup consisting of a test for one gene, a test for more than one gene,a test for related genes, a test for genes associated with a specifiedclinical outcome and a gene screen test.
 3. An instrument according toclaim 1 comprising at least one additional element selected from thegroup consisting of a collection element, an assessment element, alabeling element, a billing element, a recording element, a trainingelement, a quality control element, and an indemnification element. 4.An instrument according to claim 3 wherein said additional elementcomprises an assessment element.
 5. An instrument according to claim 3wherein said additional element comprises a collection element.
 6. Aninstrument according to claim 3 wherein said additional elementscomprise an assessment element and a collection element.
 7. Aninstrument according to claim 6, additionally comprising at least oneelement selected from the group consisting of a labeling element, abilling element, a recording element, a training element, a qualitycontrol element and an indemnification element.
 8. An instrument forobtaining from an individual informed consent to a genetic test, saidinstrument comprising: (a) an information element; (b) an instructionelement, integrated with said information element; (c) a certificationelement, integrated with said instruction and said information elements;(d) an assessment element, integrated with said information and saidinstruction elements; and (e) a collection element, integrated with saidinformation and said instruction elements.
 9. An instrument according toclaim 8 wherein said genetic test is selected from the group consistingof a test for one gene, a test for more than one gene, a test forrelated genes, a test for genes associated with a specified clinicaloutcome and a gene screen test.
 10. A method for obtaining informedconsent to a genetic test from an individual comprising the steps of:(a) procuring an integrated instrument for obtaining informed consent tothe genetic test, said instrument including an information element, aninstruction element integrated with said information element, and acertification element integrated with said information and saidinstruction elements; (b) conveying to the individual informationconcerning said genetic test using said information element; (c)instructing an individual according to the directions contained in saidinstruction element; and (d) certifying the individual's consent forsaid test using said certification element.
 11. The method according toclaim 10, wherein said integrated instrument additionally includes acollection element integrated with said information and said instructionelements, and said method comprises the additional step of collecting apersonal medical history and family history using said collectionelement.
 12. The method according to claim 10 wherein said integratedinstrument additionally includes an assessment element integrated withsaid information and said instruction elements, and said methodcomprises the additional step of assessing the individual's retention orcomprehension of the information using said assessment element.
 13. Themethod according to claim 10 wherein said integrated instrumentadditionally includes a labeling element integrated with saidinformation and said instruction elements, and said method includes theadditional step of labeling a sample with the identity of the individualusing said labeling element.
 14. The method according to claim 10wherein said integrated instrument additionally includes a recordingelement integrated with said information and said instruction elements,and said method includes the additional step of recording informationconcerning the informed consent process using said recording element.15. A method for obtaining informed consent to a genetic test from anindividual comprising the steps of: (a) procuring an integratedinstrument for informed consent to a genetic test, said instrumentincluding an information element, an instruction element integrated withsaid information element, a certification element integrated with saidinformation and said instruction elements, a collection elementintegrated with said information and said instruction elements, and anassessment element integrated with said information and said instructionelements; (b) conveying to the individual information concerning saidgenetic test using said information element; (c) instructing anindividual according to the directions contained in said instructionelement; (d) certifying the individual's consent for said test usingsaid certification element; (e) collecting a personal medical historyand family history using said collection element; and (f) assessing theindividual's retention or comprehension of the information using saidassessment element.
 16. The method according to claim 10 wherein saidgenetic test is selected from the group consisting of a test for onegene, a test for more than one gene, a test for related genes, a testfor genes associated with a specified clinical outcome and a gene screentest.
 17. The method according to claim 15 wherein said genetic test isselected from the group consisting of a test for one gene, a test formore than one gene, a test for related genes, a test for genesassociated with a specified clinical outcome and a gene screen test.